TRPM8 antagonists and their use in treatments

ABSTRACT

Compounds of Formula I are useful as antagonists of TRPM8. Such compounds are useful in treating a number of TRPM8 mediated disorders and conditions and may be used to prepare medicaments and pharmaceutical compositions useful for treating such disorders and conditions. Examples of such disorders include, but are not limited to, migraines and neuropathic pain. Compounds of Formula I have the following structure: 
                         
where the definitions of the variables are provided herein.

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/500,843, filed on Jun. 24, 2011, which is hereby incorporated byreference in its entirety and for all purposes as if fully set forthherein.

FIELD OF THE INVENTION

The present invention relates to compounds that have TRPM8 antagonistproperties and are useful in preparing medicaments and compositions andin treating diseases and conditions such as those mediated by TRPM8. Thecompounds and compositions may be used to treat various diseases orconditions modulated by TRPM8 such as, but not limited to, migraines andneuropathic pain.

BACKGROUND OF THE INVENTION

Cold sensation is derived from activation of the somatosensory system bya cold stimulus. Calcium imaging and patch clamp experiments indissociated trigeminal and dorsal root ganglia neurons have revealedcold stimuli induced calcium influx, suggesting the direct opening of acalcium-permeable ion channels by cold (Thut et al., 2003; Reid, 2005).A recently cloned non-selective cation channel, TRPM8 (transientreceptor potential melastatin 8) or trp-p8 (identified as aprostate-specific gene, up-regulated in prostate cancer and othermalignancies, (Tsavaler et al., 2001)) is activated by cold stimulus of10 to 24° C. temperature (McKemy et al., 2002; Peier et al., 2002). Inaddition, TRPM8 is also activated by compounds that elicit coolsensation such as menthol, icilin (AG-3-5) (McKemy et al., 2002), andthe endogenous lipid PIP₂ (Rohacs et al., 2005). Correlating with thecold sensitivity of both A delta and C-fibers, TRPM8 is highly expressedin sensory neurons of the trigeminal and dorsal root ganglia (McKemy etal., 2002; Peier et al., 2002; Thut et al., 2003). TRPM8 is alsoexpressed in nerve fibers innervating urinary bladder in guinea pigs(Tsukimi et al., 2005) and humans (Mukerji et al., 2006) and believed tocontribute to the bladder hypersensitivity.

Activation mechanism of TRPM8 by menthol and icilin appears to differ.Icilin requires calcium for robust activation of TRPM8, whereas mentholand cold do not (Chuang et al., 2004). Typically, activation by allthese agonists follows a period of calcium-dependent desensitization.The domain swap analysis of chicken and rat TRPM8 and further mutationalstudies revealed that determinants of icilin sensitivity map to a regionof TRPM8 that corresponds to the capsaicin binding site in TRPV1transmembrane domain 3 to 4 region (Chuang et al., 2004).

Cold allodynia and mechanical hyperalgesia are associated withneuropathic pain in humans and in rodent models of neuropathic andchemotherapy-induced pain. TRPM8 is shown to mediate the analgesia byagonists such as menthol and icilin (by desensitization of the receptor)during experimental neuropathic pain in rodents (Proudfoot et al.,2006). Further, attenuation of cold sensation and cold allodynia afterchronic constriction injury model of neuropathic pain in TRPM8 knockoutmice (Colburn et al., 2007; Dhaka et al., 2007) suggests thatantagonists of TRPM8 may be considered as pain therapeutics forchemotherapy-induced pain, neuropathic pain and bladder disorders.

Mint oil that contains menthol, an agonist of TRPM8 has been reported toalleviate pain in post-herpetic neuralgia (Davies et al., 2002), aneuropathic pain condition. Furthermore, oral or intracerebroventricularinjection of menthol decreased nociceptive responses to hot-plate testand acetic acid-induced writhing in mice (Galeotti et al., 2002). Theseresponses are believed to be mediated by the activation anddesensitization of the TRPM8. These observations and the knockout micestudies indicate that TRPM8 modulation by antagonists might bebeneficial for patients experiencing neuropathic pain.

A need exists for TRPM8 antagonist compounds that can be used to treatdiseases and conditions mediated by TRPM8 such as, but not limited to,migraines and neuropathic pain and those other conditions describedherein.

SUMMARY OF THE INVENTION

The present invention comprises a new class of compounds useful in thetreatment of diseases, such as TRPM8-mediated diseases and othermaladies, such as inflammatory or neuropathic pain and diseasesinvolving sensory nerve function such as asthma, rheumatoid arthritis,osteoarthritis, inflammatory bowel disorders, urinary incontinence,migraine and psoriasis. In particular, the compounds of the inventionare useful for the treatment of acute, inflammatory and neuropathicpain, dental pain, general headache, migraine, cluster headache,mixed-vascular and non-vascular syndromes, tension headache, generalinflammation, arthritis, rheumatic diseases, osteoarthritis,inflammatory bowel disorders, anxiety, depression, inflammatory eyedisorders, inflammatory or unstable bladder disorders, psoriasis, skincomplaints with inflammatory components, chronic inflammatoryconditions, inflammatory pain and associated hyperalgesia and allodynia,neuropathic pain and associated hyperalgesia and allodynia, diabeticneuropathy pain, causalgia, sympathetically maintained pain,deafferentation syndromes, asthma, epithelial tissue damage ordysfunction, herpes simplex, disturbances of visceral motility atrespiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritus, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladderdisorders. Accordingly, the invention also comprises pharmaceuticalcompositions comprising the compounds, methods for the treatment ofTRPM8-receptor-mediated diseases, such as inflammatory or neuropathicpain, asthma, rheumatoid arthritis, osteoarthritis, inflammatory boweldisorders, urinary incontinence, migraine and psoriasis diseases, usingthe compounds and compositions of the invention, and intermediates andprocesses useful for the preparation of the compounds of the invention.

In one aspect, the compounds of the invention are represented by thefollowing general structure:

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴,R⁵, R⁶, X¹, X², m and n are defined below.

In another aspect, the invention provides compounds of Formula I havingthe structure:

a pharmaceutically-acceptable salt thereof, a tautomer thereof, apharmaceutically-acceptable salt of the tautomer, a stereoisomerthereof, or a mixture thereof, wherein:

m is 0, 1, 2 or 3;

n is 0 or 1;

X¹ is C(R⁴) or N;

X² is CH, CF, or N;

R¹ is C₁₋₆alk or a direct-bonded, C₁₋₂alk-linked, C₁₋₂alkO-linked,saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6- or7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ringcontaining 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, butcontaining no more than one O or S atom, the C₁₋₆alk and ring beingsubstituted by 0, 1, 2 or 3 substituents independently selected fromhalo, oxo, C₁₋₆alk, C₁₋₆alkOH, C₁₋₆alk-C(═O)R^(a), C₁₋₆alk-C(═O)OR^(a),C₁₋₄haloalk, cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a),—SR^(a), ═S, —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(a),—N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(a),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a) and—NR^(a)C₂₋₆alkOR^(a), wherein the ring is additionally substituted by 0or 1 directly bonded, SO₂ linked, C(═O) linked or CH₂ linked saturated,partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-memberedmonocyclic ring containing 0, 1, 2, 3 or 4 heteroatoms selected from N,O and S, but containing no more than one O or S atom, and substituted by0, 1, 2 or 3 groups selected from halo, oxo, C₁₋₆alk, C₁₋₄haloalk,cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a), and —N(R^(a))C(═O)R^(a);

R² is H, halo, cyano, R^(c), —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a) and—NR^(a)C₂₋₆alkOR^(a); or R² is C₁₋₆alk substituted by 0, 1, 2 or 3substituents selected from C₁₋₄haloalk, halo, cyano, nitro, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a) and—NR^(a)C₂₋₆alkOR^(a), or R² is C₁₋₆alk substituted by 0, 1, 2 or 3 halosubstituents and additionally substituted by 0 or 1 substituentsselected from R^(c);

R³ is H, C₁₋₈alk, C₁₋₈alkOH, C₁₋₄haloalk, halo, cyano, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a) or—NR^(a)C₂₋₆alkOR^(a);

R⁴ is independently, at each instance, H, C₁₋₆alk, —C₁₋₃haloalk,—OC₁₋₆alk, —OC₁₋₃haloalk, —N(C₁₋₆alk)C₁₋₆alk, —NHC₁₋₆alk,—NC(═O)C₁₋₆alk, —N(C₁₋₆alk)C₁₋₆alk, F, Cl, Br, CN, OH or NH₂; or R³ andR⁴ together form a four-atom unsaturated bridge containing 0 or 1 Natoms, wherein the bridge is substituted by 0, 1 or 2 R⁵ substituents;

R⁵ is independently, in each instance, halo, OR^(a), CH₃ or CF₃;

R⁶ is F, C₁₋₆alk, or OR^(a);

R^(a) is independently, at each instance, H or R^(b);

R^(b) is independently, at each instance, phenyl, benzyl or C₁₋₆alk, thephenyl, benzyl and C₁₋₆alk being substituted by 0, 1, 2 or 3substituents selected from halo, oxo, C₁₋₄alk, C₁₋₃haloalk, —OC₁₋₄alk,—OH, —NH₂, —OC₁₋₄alk, —OC₁₋₄haloalk, —NHC₁₋₄alk, and —N(C₁₋₄alk)C₁₋₄alk;and

R^(c) is independently, at each instance, a saturated, partiallysaturated or unsaturated 4-, 5- or 6-membered monocyclic ring containing0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein theC₁₋₆alkyl and ring are substituted by 0 or 1 oxo groups substituted by0, 1, 2 or 3 substituents selected from C₁₋₈alk, C₁₋₄haloalk, halo andcyano.

In some such embodiments, the compound of Formula I has the Formula IA:

In some embodiments of the compounds of Formula IA,

X² is selected from CH or N;

R¹ is selected from C₁₋₆alk or a direct-bonded, C₁₋₂alk-linked,C₁₋₂alkO-linked, saturated, partially-saturated or unsaturated 3-, 4-,5-, 6- or 7-membered monocyclic or 7-, 8-, 9-, 10- or 11-memberedbicyclic ring containing 0, 1, 2, 3 or 4 heteroatoms selected from N, Oand S, but containing no more than one O or S atom, the C₁₋₆alk and ringbeing substituted by 0, 1, 2 or 3 substituents independently selectedfrom halo, oxo, C₁₋₆alk, C₁₋₄haloalk, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkNR^(a)R^(a) and —NR^(a)C₂₋₆alkOR^(a), wherein the ring isadditionally substituted by 0 or 1 directly bonded, SO₂ linked, C(═O)linked or CH₂ linked saturated, partially-saturated or unsaturated 3-,4-, 5-, 6- or 7-membered monocyclic ring substituted by 0, 1, 2 or 3groups selected from halo, C₁₋₆alk, C₁₋₄haloalk, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —NR^(a)R^(a), and —N(R^(a))C(═O)R^(a);

R³ is H, C₁₋₈alk, C₁₋₄haloalk, halo, cyano, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a) or—NR^(a)C₂₋₆alkOR^(a); or R³ and R⁴ together form a four-atom unsaturatedbridge containing 0 or 1 N atoms, wherein the bridge is substituted by0, 1 or 2 R⁵ substituents;

R⁵ is independently, in each instance, F, CH₃ or CF₃; and

R⁶ is F.

In another aspect, the invention provides pharmaceutical compositionsthat include the compound of any of the embodiments or thepharmaceutically-acceptable salt thereof, the tautomer thereof, thepharmaceutically-acceptable salt of the tautomer, or the mixturethereof, and a pharmaceutically-acceptable diluent or carrier.

In yet another aspect, the invention provides methods of treating acute,inflammatory and neuropathic pain, dental pain, general headache,migraine, cluster headache, mixed-vascular and non-vascular syndromes,tension headache, general inflammation, arthritis, rheumatic diseases,osteoarthritis, inflammatory bowel disorders, depression, anxiety,inflammatory eye disorders, inflammatory or unstable bladder disorders,psoriasis, skin complaints with inflammatory components, chronicinflammatory conditions, inflammatory pain and associated hyperalgesiaand allodynia, neuropathic pain and associated hyperalgesia andallodynia, diabetic neuropathy pain, causalgia, sympatheticallymaintained pain, deafferentation syndromes, asthma, epithelial tissuedamage or dysfunction, herpes simplex, disturbances of visceral motilityat respiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritus, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladder disordersin a subject. Such methods typically include administering the compoundaccording to any of the embodiments or the pharmaceutically-acceptablesalt thereof, the tautomer thereof, the pharmaceutically-acceptable saltof the tautomer, or the mixture thereof to the subject. In some suchembodiments, the subject is suffering from neuropathic paid whereas inother embodiments the subject is suffering from migraines or migrainepain.

The compounds of the invention may also be used to preparepharmaceutical compositions and medicaments. Therefore, in someembodiments, the invention provides the use of the compound according toany of the embodiments or the pharmaceutically-acceptable salt thereof,the tautomer thereof, the pharmaceutically-acceptable salt of thetautomer, or the mixture thereof in the preparation of a medicament.

In another aspect, the invention provides the use of the compoundaccording to any of the embodiments or the pharmaceutically-acceptablesalt thereof, the tautomer thereof, the pharmaceutically-acceptable saltof the tautomer, or the mixture thereof for treating acute, inflammatoryand neuropathic pain, dental pain, general headache, migraine, clusterheadache, mixed-vascular and non-vascular syndromes, tension headache,general inflammation, arthritis, rheumatic diseases, osteoarthritis,inflammatory bowel disorders, depression, anxiety, inflammatory eyedisorders, inflammatory or unstable bladder disorders, psoriasis, skincomplaints with inflammatory components, chronic inflammatoryconditions, inflammatory pain and associated hyperalgesia and allodynia,neuropathic pain and associated hyperalgesia and allodynia, diabeticneuropathy pain, causalgia, sympathetically maintained pain,deafferentation syndromes, asthma, epithelial tissue damage ordysfunction, herpes simplex, disturbances of visceral motility atrespiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritus, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladder disordersin a subject. In some such embodiments, the compound is used to treatneuropathic paid. In other embodiments, the compound is used to treatmigraines or migraine pain

The foregoing merely summarizes certain aspects of the invention and isnot intended, nor should it be construed, as limiting the invention inany way. All patents, patent applications and other publications recitedherein are hereby incorporated by reference in their entirety.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention may have in general several asymmetriccenters and are typically depicted in the form of racemic mixtures. Thisinvention is intended to encompass racemic mixtures, partially racemicmixtures and separate enantiomers and diasteromers.

Unless otherwise specified, the following definitions apply to termsfound in the specification and claims:

“C_(α-β)alk” means an alkyl group comprising a minimum of α and amaximum of β carbon atoms in a branched, cyclical or linear relationshipor any combination of the three, wherein α and β represent integers. Thealkyl groups described in this section may also contain one or twodouble or triple bonds. A designation of C₀alk indicates a direct bond.Examples of C₁₋₆alkyl include, but are not limited to the following:

Where the term “C_(α-β)alkyl” and “C_(α-β)cycloalkyl” are used, theyrelate to acyclic saturated alkyls and cyclic saturated alkyls,respectively.

“Benzo group”, alone or in combination, means the divalent radicalC₄H₄═, one representation of which is —CH═CH—CH═CH—, that when vicinallyattached to another ring forms a benzene-like ring—for exampletetrahydronaphthylene, indole and the like.

The terms “oxo” and “thioxo” represent the groups ═O (as in carbonyl)and ═S (as in thiocarbonyl), respectively.

The term “cyano” refers to a nitrile group which may be written as —C≡N.

“Halo” or “halogen” means a halogen atoms selected from F, Cl, Br and I.

“C_(V-W)haloalk” means an alk group, as described above, wherein anynumber, but at least one, of the hydrogen atoms attached to the alkchain are replaced by F, Cl, Br or I.

The group N(R^(a))R^(a) and the like include substituents where the twoR^(a) groups together form a ring, optionally including a N, O or Satom, and include groups such as:

The group N(C_(α-β)alk)C_(α-β)alk, wherein α and β are as defined above,include substituents where the two C_(α-β)alk groups together form aring, optionally including a N, O or S atom, and include groups such as:

“Heterocycle” means a ring comprising at least one carbon atom and atleast one other atom selected from N, O and S. Examples of heterocyclesthat may be found in the claims include, but are not limited to, thefollowing:

“Pharmaceutically-acceptable salt” means a salt prepared by conventionalmeans, and are well known by those skilled in the art. The“pharmacologically acceptable salts” include basic salts of inorganicand organic acids, including but not limited to hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid,ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaricacid, citric acid, lactic acid, fumaric acid, succinic acid, maleicacid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid andthe like. When compounds of the invention include an acidic functionsuch as a carboxy group, then suitable pharmaceutically acceptablecation pairs for the carboxy group are well known to those skilled inthe art and include alkaline, alkaline earth, ammonium, quaternaryammonium cations and the like. For additional examples of“pharmacologically acceptable salts,” see infra and Berge et al., J.Pharm. Sci. 66:1 (1977).

“Saturated, partially-saturated or unsaturated” includes substituentssaturated with hydrogens, substituents completely unsaturated withhydrogens and substituents partially saturated with hydrogens.

“Leaving group” generally refers to groups readily displaceable by anucleophile, such as an amine, a thiol or an alcohol nucleophile. Suchleaving groups are well known in the art. Examples of such leavinggroups include, but are not limited to, N-hydroxysuccinimide,N-hydroxybenzotriazole, halides, triflates, tosylates and the like.Preferred leaving groups are indicated herein where appropriate.

“Protecting group” generally refers to groups well known in the artwhich are used to prevent selected reactive groups, such as carboxy,amino, hydroxy, mercapto and the like, from undergoing undesiredreactions, such as nucleophilic, electrophilic, oxidation, reduction andthe like. Preferred protecting groups are indicated herein whereappropriate. Examples of amino protecting groups include, but are notlimited to, aralkyl, substituted aralkyl, cycloalkenylalkyl andsubstituted cycloalkenyl alkyl, allyl, substituted allyl, acyl,alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples ofaralkyl include, but are not limited to, benzyl, ortho-methylbenzyl,trityl and benzhydryl, which can be optionally substituted with halogen,alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts,such as phosphonium and ammonium salts. Examples of aryl groups includephenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl),phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl orsubstituted cycloalkylenylalkyl radicals, preferably have 6-10 carbonatoms, include, but are not limited to, cyclohexenyl methyl and thelike. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups includebenzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl,substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloro acetyl,phthaloyl and the like. A mixture of protecting groups can be used toprotect the same amino group, such as a primary amino group can beprotected by both an aralkyl group and an aralkoxycarbonyl group. Aminoprotecting groups can also form a heterocyclic ring with the nitrogen towhich they are attached, for example, 1,2-bis(methylene)benzene,phthalimidyl, succinimidyl, maleimidyl and the like and where theseheterocyclic groups can further include adjoining aryl and cycloalkylrings. In addition, the heterocyclic groups can be mono-, di- ortri-substituted, such as nitrophthalimidyl. Amino groups may also beprotected against undesired reactions, such as oxidation, through theformation of an addition salt, such as hydrochloride, toluenesulfonicacid, trifluoroacetic acid and the like. Many of the amino protectinggroups are also suitable for protecting carboxy, hydroxy and mercaptogroups. For example, aralkyl groups. Alkyl groups are also suitablegroups for protecting hydroxy and mercapto groups, such as tert-butyl.

Silyl protecting groups are silicon atoms optionally substituted by oneor more alkyl, aryl and aralkyl groups. Suitable silyl protecting groupsinclude, but are not limited to, trimethylsilyl, triethylsilyl,triisopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl,1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane anddiphenylmethylsilyl. Silylation of an amino groups provide mono- ordi-silylamino groups. Silylation of aminoalcohol compounds can lead to aN,N,O-trisilyl derivative. Removal of the silyl function from a silylether function is readily accomplished by treatment with, for example, ametal hydroxide or ammonium fluoride reagent, either as a discretereaction step or in situ during a reaction with the alcohol group.Suitable silylating agents are, for example, trimethylsilyl chloride,tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride,diphenylmethyl silyl chloride or their combination products withimidazole or DMF. Methods for silylation of amines and removal of silylprotecting groups are well known to those skilled in the art. Methods ofpreparation of these amine derivatives from corresponding amino acids,amino acid amides or amino acid esters are also well known to thoseskilled in the art of organic chemistry including amino acid/amino acidester or aminoalcohol chemistry.

Protecting groups are removed under conditions which will not affect theremaining portion of the molecule. These methods are well known in theart and include acid hydrolysis, hydrogenolysis and the like. Apreferred method involves removal of a protecting group, such as removalof a benzyloxycarbonyl group by hydrogenolysis utilizing palladium oncarbon in a suitable solvent system such as an alcohol, acetic acid, andthe like or mixtures thereof. A t-butoxycarbonyl protecting group can beremoved utilizing an inorganic or organic acid, such as HCl ortrifluoroacetic acid, in a suitable solvent system, such as dioxane ormethylene chloride. The resulting amino salt can readily be neutralizedto yield the free amine. Carboxy protecting group, such as methyl,ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can beremoved under hydrolysis and hydrogenolysis conditions well known tothose skilled in the art.

It should be noted that compounds of the invention may contain groupsthat may exist in tautomeric forms, such as cyclic and acyclic amidineand guanidine groups, heteroatom substituted heteroaryl groups (Y′═O, S,NR), and the like, which are illustrated in the following examples:

and though one form is named, described, displayed and/or claimedherein, all the tautomeric forms are intended to be inherently includedin such name, description, display and/or claim.

Prodrugs of the compounds of this invention are also contemplated bythis invention. A prodrug is an active or inactive compound that ismodified chemically through in vivo physiological action, such ashydrolysis, metabolism and the like, into a compound of this inventionfollowing administration of the prodrug to a patient. The suitabilityand techniques involved in making and using prodrugs are well known bythose skilled in the art. For a general discussion of prodrugs involvingesters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) andBundgaard Design of Prodrugs, Elsevier (1985). Examples of a maskedcarboxylate anion include a variety of esters, such as alkyl (forexample, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl(for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (forexample, pivaloyloxymethyl). Amines have been masked asarylcarbonyloxymethyl substituted derivatives which are cleaved byesterases in vivo releasing the free drug and formaldehyde (Bungaard J.Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, suchas imidazole, imide, indole and the like, have been masked withN-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)).Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloanand Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acidprodrugs, their preparation and use.

The specification and claims contain listing of species using thelanguage like “selected from . . . and . . . ” and “is . . . or . . . ”(sometimes referred to as Markush groups). When this language is used inthis application, unless otherwise stated it is meant to include thegroup as a whole, or any single members thereof, or any subgroupsthereof. The use of this language is merely for shorthand purposes andis not meant in any way to limit the removal of individual elements orsubgroups as needed.

One aspect of the current invention relates to compounds having thegeneral structure:

or any pharmaceutically-acceptable salt thereof, wherein:

m is 0, 1, 2 or 3;

n is 0 or 1;

X¹ is C(R⁴) or N;

X² is C or N;

Y is NH or O;

R¹ is selected from C₁₋₆alk or a direct-bonded, C₁₋₂alk-linked,C₁₋₂alkO-linked, saturated, partially-saturated or unsaturated 3-, 4-,5-, 6- or 7-membered monocyclic or 7-, 8-, 9-, 10- or 11-memberedbicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S,but containing no more than one O or S atom, the C₁₋₆alk and ring beingsubstituted by 0, 1, 2 or 3 substituents independently selected fromhalo, oxo, C₁₋₆alk, C₁₋₄haloalk, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkNR^(a)R^(a) and —NR^(a)C₂₋₆alkOR^(a), wherein the ring isadditionally substituted by 0 or 1 directly bonded, SO₂ linked, C(═O)linked or CH₂ linked saturated, partially-saturated or unsaturated 3-,4-, 5-, 6- or 7-membered monocyclic ring substituted by 0, 1, 2 or 3groups selected from halo, C₁₋₆alk, C₁₋₄haloalk, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —NR^(a)R^(a), and —N(R^(a))C(═O)R^(a);

R² is selected from H, halo, cyano, R^(c), —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a) and—NR^(a)C₂₋₆alkOR^(a); or R² is C₁₋₆alk substituted by 0, 1, 2 or 3substituents selected from C₁₋₄haloalk, halo, cyano, nitro, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a) and—NR^(a)C₂₋₆alkOR^(a), or R² is C¹⁻⁶alk substituted by 0, 1, 2 or 3 halosubstituents and additionally substituted by 0 or 1 substituentsselected from R^(c);

R³ is H, C₁₋₈alk, C₁₋₄haloalk, halo, cyano, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a) or—NR^(a)C₂₋₆alkOR^(a);

R⁴ is independently, at each instance, H, C₁₋₆alk, —C₁₋₃haloalk,—OC₁₋₆alk, —OC₁₋₃haloalk, —N(C₁₋₆alk)C₁₋₆alk, —NHC₁₋₆alk,—NC(═O)C₁₋₆alk, —N(C₁₋₆alk)C₁₋₆alk, F, Cl, Br, CN, OH or NH₂; or R³ andR⁴ together form a four-atom unsaturated bridge containing 0 or 1 Natoms, wherein the bridge is substituted by 0, 1 or 2 R⁵ substituents;

R⁵ is independently, in each instance, F, CH₃ or CF₃;

R⁶ is F;

R^(a) is independently, at each instance, H or R^(b);

R^(b) is independently, at each instance, phenyl, benzyl or C₁₋₆alk, thephenyl, benzyl and C₁₋₆alk being substituted by 0, 1, 2 or 3substituents selected from halo, oxo, C₁₋₄alk, C₁₋₃haloalk, —OC₁₋₄alk,—OH, —NH₂, —OC₁₋₄alk, —OC₁₋₄haloalk, —NHC₁₋₄alk, and —N(C₁₋₄alk)C₁₋₄alk;and

R^(c) is independently, at each instance, a saturated, partiallysaturated or unsaturated 4-, 5- or 6-membered monocyclic ring containing0, 1, 2, 3 or 4 atoms selected from N, O and S, wherein the C₁₋₆alkyland ring are substituted by 0 or 1 oxo groups substituted by 0, 1, 2 or3 substituents selected from C₁₋₈alk, C₁₋₄haloalk, halo and cyano.

Another aspect of the current invention relates to compounds having thegeneral structure:

or any pharmaceutically-acceptable salt thereof, wherein:

m is 0, 1, 2 or 3;

n is 0 or 1;

X¹ is C(R⁴) or N;

R¹ is selected from C₁₋₆alk or a direct-bonded, C₁₋₂alk-linked,C₁₋₂alkO-linked, saturated, partially-saturated or unsaturated 3-, 4-,5-, 6- or 7-membered monocyclic or 7-, 8-, 9-, 10- or 11-memberedbicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S,but containing no more than one O or S atom, the C₁₋₆alk and ring beingsubstituted by 0, 1, 2 or 3 substituents independently selected fromhalo, oxo, C₁₋₆alk, C₁₋₄haloalk, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkNR^(a)R^(a) and —NR^(a)C₂₋₆alkOR^(a), wherein the ring isadditionally substituted by 0 or 1 directly bonded, SO₂ linked, C(═O)linked or CH₂ linked saturated, partially-saturated or unsaturated 3-,4-, 5-, 6- or 7-membered monocyclic ring substituted by 0, 1, 2 or 3groups selected from halo, C₁₋₆alk, C₁₋₄haloalk, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —NR^(a)R^(a), and —N(R^(a))C(═O)R^(a);

R² is selected from H, halo, cyano, R^(c), —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a) and—NR^(a)C₂₋₆alkOR^(a); or R² is C₁₋₆alk substituted by 0, 1, 2 or 3substituents selected from C₁₋₄haloalk, halo, cyano, nitro, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a) and—NR^(a)C₂₋₆alkOR^(a), or R² is C¹⁻⁶alk substituted by 0, 1, 2 or 3 halosubstituents and additionally substituted by 0 or 1 substituentsselected from R^(c);

R³ is H, C₁₋₈alk, C₁₋₄haloalk, halo, cyano, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a) or—NR^(a)C₂₋₆alkOR^(a);

R⁴ is independently, at each instance, H, C₁₋₆alk, —C₁₋₃haloalk,—OC₁₋₆alk, —OC₁₋₃haloalk, —N(C₁₋₆alk)C₁₋₆alk, —NHC₁₋₆alk,—NC(═O)C₁₋₆alk, —N(C₁₋₆alk)C₁₋₆alk, F, Cl, Br, CN, OH or NH₂; or R³ andR⁴ together form a four-atom unsaturated bridge containing 0 or 1 Natoms, wherein the bridge is substituted by 0, 1 or 2 R⁵ substituents;

R⁵ is independently, in each instance, F, CH₃ or CF₃;

R⁶ is F;

R^(a) is independently, at each instance, H or R^(b);

R^(b) is independently, at each instance, phenyl, benzyl or C₁₋₆alk, thephenyl, benzyl and C₁₋₆alk being substituted by 0, 1, 2 or 3substituents selected from halo, oxo, C₁₋₄alk, C₁₋₃haloalk, —OC₁₋₄alk,—OH, —NH₂, —OC₁₋₄alk, —OC₁₋₄haloalk, —NHC₁₋₄alk, and —N(C₁₋₄alk)C₁₋₄alk;and

R^(c) is independently, at each instance, a saturated, partiallysaturated or unsaturated 4-, 5- or 6-membered monocyclic ring containing0, 1, 2, 3 or 4 atoms selected from N, O and S, wherein the C₁₋₆alkyland ring are substituted by 0 or 1 oxo groups substituted by 0, 1, 2 or3 substituents selected from C₁₋₈alk, C₁₋₄haloalk, halo and cyano.

Another aspect of the current invention relates to compounds having thegeneral structure:

or any pharmaceutically-acceptable salt thereof, wherein:

m is 0, 1, 2 or 3;

n is 0 or 1;

X² is C or N;

R¹ is selected from C₁₋₆alk or a direct-bonded, C₁₋₂alk-linked,C₁₋₂alkO-linked, saturated, partially-saturated or unsaturated 3-, 4-,5-, 6- or 7-membered monocyclic or 7-, 8-, 9-, 10- or 11-memberedbicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S,but containing no more than one O or S atom, the C₁₋₆alk and ring beingsubstituted by 0, 1, 2 or 3 substituents independently selected fromhalo, oxo, C₁₋₆alk, C₁₋₄haloalk, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkNR^(a)R^(a) and —NR^(a)C₂₋₆alkOR^(a), wherein the ring isadditionally substituted by 0 or 1 directly bonded, SO₂ linked, C(═O)linked or CH₂ linked saturated, partially-saturated or unsaturated 3-,4-, 5-, 6- or 7-membered monocyclic ring substituted by 0, 1, 2 or 3groups selected from halo, C₁₋₆alk, C₁₋₄haloalk, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —NR^(a)R^(a), and —N(R^(a))C(═O)R^(a);

R² is selected from H, halo, cyano, R^(c), —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a) and—NR^(a)C₂₋₆alkOR^(a); or R² is C₁₋₆alk substituted by 0, 1, 2 or 3substituents selected from C₁₋₄haloalk, halo, cyano, nitro, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a) and—NR^(a)C₂₋₆alkOR^(a), or R² is C¹⁻⁶alk substituted by 0, 1, 2 or 3 halosubstituents and additionally substituted by 0 or 1 substituentsselected from R^(c);

R³ is H, C₁₋₈alk, C₁₋₄haloalk, halo, cyano, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a) or—NR^(a)C₂₋₆alkOR^(a);

R⁴ is independently, at each instance, H, C₁₋₆alk, —C₁₋₃haloalk,—OC₁₋₆alk, —OC₁₋₃haloalk, —N(C₁₋₆alk)C₁₋₆alk, —NHC₁₋₆alk,—NC(═O)C₁₋₆alk, —N(C₁₋₆alk)C₁₋₆alk, F, Cl, Br, CN, OH or NH₂;

R⁵ is F, CH₃ or CF₃;

R⁶ is F;

R^(a) is independently, at each instance, H or R^(b);

R^(b) is independently, at each instance, phenyl, benzyl or C₁₋₆alk, thephenyl, benzyl and C₁₋₆alk being substituted by 0, 1, 2 or 3substituents selected from halo, oxo, C₁₋₄alk, C₁₋₃haloalk, —OC₁₋₄alk,—OH, —NH₂, —OC₁₋₄alk, —OC₁₋₄haloalk, —NHC₁₋₄alk, and —N(C₁₋₄alk)C₁₋₄alk;and

R^(c) is independently, at each instance, a saturated, partiallysaturated or unsaturated 4-, 5- or 6-membered monocyclic ring containing0, 1, 2, 3 or 4 atoms selected from N, O and S, wherein the C₁₋₆alkyland ring are substituted by 0 or 1 oxo groups substituted by 0, 1, 2 or3 substituents selected from C₁₋₈alk, C₁₋₄haloalk, halo and cyano.

Another aspect of the current invention relates to compounds having thegeneral structure:

or any pharmaceutically-acceptable salt thereof, wherein:

m is 0, 1, 2 or 3;

R¹ is a direct-bonded, partially-saturated or unsaturated 5- or6-membered monocyclic ring containing 1 or 2 atoms selected from N, Oand S, but containing no more than one O or S atom, the C₁₋₆alk and ringbeing substituted by 0, 1, 2 or 3 substituents independently selectedfrom halo, oxo, C₁₋₆alk, C₁₋₄haloalk and cyano;

R² is selected from F and CF₃;

R³ is CH₃, CF₃, F or Cl;

R⁴ is H or F;

R⁶ is F;

R^(a) is independently, at each instance, H or R^(b);

R^(b) is independently, at each instance, phenyl, benzyl or C₁₋₆alk, thephenyl, benzyl and C₁₋₆alk being substituted by 0, 1, 2 or 3substituents selected from halo, oxo, C₁₋₄alk, C₁₋₃haloalk, —OC₁₋₄alk,—OH, —NH₂, —OC₁₋₄alk, —OC₁₋₄haloalk, —NHC₁₋₄alk, and —N(C₁₋₄alk)C₁₋₄alk;and

R^(c) is independently, at each instance, a saturated, partiallysaturated or unsaturated 4-, 5- or 6-membered monocyclic ring containing0, 1, 2, 3 or 4 atoms selected from N, O and S, wherein the C₁₋₆alkyland ring are substituted by 0 or 1 oxo groups substituted by 0, 1, 2 or3 substituents selected from C₁₋₈alk, C₁₋₄haloalk, halo and cyano.

Another aspect of the current invention relates to compounds having thegeneral structure:

or any pharmaceutically-acceptable salt thereof, wherein:

m is 0, 1, 2 or 3;

R¹ is a direct-bonded, partially-saturated or unsaturated 5- or6-membered monocyclic ring containing 1 or 2 atoms selected from N, Oand S, but containing no more than one O or S atom, the C₁₋₆alk and ringbeing substituted by 0, 1, 2 or 3 substituents independently selectedfrom halo, oxo, C₁₋₆alk, C₁₋₄haloalk and cyano; and

R² is selected from F and CF₃.

Another aspect of the current invention relates to compounds having thegeneral structure:

or any pharmaceutically-acceptable salt thereof, wherein:

m is 0, 1, 2 or 3;

n is 0 or 1;

X¹ is C(R⁴) or N;

X² is C or N;

Y is NH or O;

R¹ is selected from C₁₋₆alk or a direct-bonded, C₁₋₂alk-linked,C₁₋₂alkO-linked, saturated, partially-saturated or unsaturated 3-, 4-,5-, 6- or 7-membered monocyclic or 7-, 8-, 9-, 10- or 11-memberedbicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S,but containing no more than one O or S atom, the C₁₋₆alk and ring beingsubstituted by 0, 1, 2 or 3 substituents independently selected fromhalo, oxo, C₁₋₆alk, C₁₋₄haloalk, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkNR^(a)R^(a) and —NR^(a)C₂₋₆alkOR^(a), wherein the ring isadditionally substituted by 0 or 1 directly bonded, SO₂ linked, C(═O)linked or CH₂ linked saturated, partially-saturated or unsaturated 3-,4-, 5-, 6- or 7-membered monocyclic ring substituted by 0, 1, 2 or 3groups selected from halo, C₁₋₆alk, C₁₋₄haloalk, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —NR^(a)R^(a), and —N(R^(a))C(═O)R^(a);

R² is selected from H, halo, cyano, R^(c), —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a) and—NR^(a)C₂₋₆alkOR^(a); or R² is C₁₋₆alk substituted by 0, 1, 2 or 3substituents selected from C₁₋₄haloalk, halo, cyano, nitro, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a) and—NR^(a)C₂₋₆alkOR^(a), or R² is C¹⁻⁶alk substituted by 0, 1, 2 or 3 halosubstituents and additionally substituted by 0 or 1 substituentsselected from R^(c);

R³ is H, C₁₋₈alk, C₁₋₄haloalk, halo, cyano, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a) or—NR^(a)C₂₋₆alkOR^(a);

R⁴ is independently, at each instance, H, C₁₋₆alk, —C₁₋₃haloalk,—OC₁₋₆alk, —OC₁₋₃haloalk, —N(C₁₋₆alk)C₁₋₆alk, —NHC₁₋₆alk,—NC(═O)C₁₋₆alk, —N(C₁₋₆alk)C₁₋₆alk, F, Cl, Br, CN, OH or NH₂;

R⁵ is F, CH₃ or CF₃;

R⁶ is F;

R^(a) is independently, at each instance, H or R^(b);

R^(b) is independently, at each instance, phenyl, benzyl or C₁₋₆alk, thephenyl, benzyl and C₁₋₆alk being substituted by 0, 1, 2 or 3substituents selected from halo, oxo, C₁₋₄alk, C₁₋₃haloalk, —OC₁₋₄alk,—OH, —NH₂, —OC₁₋₄alk, —OC₁₋₄haloalk, —NHC₁₋₄alk, and —N(C₁₋₄alk)C₁₋₄alk;and

R^(c) is independently, at each instance, a saturated, partiallysaturated or unsaturated 4-, 5- or 6-membered monocyclic ring containing0, 1, 2, 3 or 4 atoms selected from N, O and S, wherein the C₁₋₆alkyland ring are substituted by 0 or 1 oxo groups substituted by 0, 1, 2 or3 substituents selected from C₁₋₈alk, C₁₋₄haloalk, halo and cyano.

In another embodiment, in conjunction with any above or belowembodiments, R¹ is C₁₋₆alk substituted by 0, 1, 2 or 3 substituentsindependently selected from halo, oxo, C₁₋₆alk, C₁₋₄haloalk, cyano,nitro, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a),—SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(a),—N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(a),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a) and—NR^(a)C₂₋₆alkOR^(a).

In another embodiment, in conjunction with any above or belowembodiments, R¹ is C₁₋₂alk-linked saturated, partially-saturated orunsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring containing 0,1, 2, 3 or 4 atoms selected from N, O and S, but containing no more thanone O or S atom, the ring being substituted by 0, 1, 2 or 3 substituentsindependently selected from halo, oxo, C₁₋₆alk, C₁₋₄haloalk, cyano,nitro, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a),—SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(a),—N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(a),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a) and—NR^(a)C₂₋₆alkOR^(a).

In another embodiment, in conjunction with any above or belowembodiments, R¹ is a direct-bonded saturated, partially-saturated orunsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 7-, 8-, 9-, 10-or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selectedfrom N, O and S, but containing no more than one O or S atom, the ringbeing substituted by 0, 1, 2 or 3 substituents independently selectedfrom halo, oxo, C₁₋₆alk, C₁₋₄haloalk, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkNR^(a)R^(a) and —NR^(a)C₂₋₆alkOR^(a), wherein the ring isadditionally substituted by 0 or 1 directly bonded, SO₂ linked, C(═O)linked or CH₂ linked saturated, partially-saturated or unsaturated 3-,4-, 5-, 6- or 7-membered monocyclic ring substituted by 0, 1, 2 or 3groups selected from halo, C₁₋₆alk, C₁₋₄haloalk, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —NR^(a)R^(a), and —N(R^(a))C(═O)R^(a).

In another embodiment, in conjunction with any above or belowembodiments, R¹ is a direct-bonded partially-saturated or unsaturated 5-or 6-membered monocyclic ring containing 1, 2, 3 or 4 atoms selectedfrom N, O and S, but containing no more than one O or S atom, the ringbeing substituted by 0, 1, 2 or 3 substituents independently selectedfrom halo, oxo, C₁₋₆alk, C₁₋₄haloalk, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkNR^(a)R^(a) and —NR^(a)C₂₋₆alkOR^(a).

In another embodiment, in conjunction with any above or belowembodiments, R¹ is a direct-bonded partially-saturated or unsaturated6-membered monocyclic ring containing 1 or 2 N atoms, substituted by 0,1, 2 or 3 substituents independently selected from halo, oxo, C₁₋₆alk,C₁₋₄haloalk, cyano and —OR^(a).

In another embodiment, in conjunction with any above or belowembodiments, R¹ is a direct-bonded unsaturated 10-membered bicyclic ringcontaining 1 or 2 N atoms, substituted by 0, 1, 2 or 3 substituentsindependently selected from halo, oxo, C₁₋₆alk, C₁₋₄haloalk, cyano and—OR^(a).

Another aspect of the invention relates to a method of treating acute,inflammatory and neuropathic pain, dental pain, general headache,migraine, cluster headache, mixed-vascular and non-vascular syndromes,tension headache, general inflammation, arthritis, rheumatic diseases,osteoarthritis, inflammatory bowel disorders, depression, anxiety,inflammatory eye disorders, inflammatory or unstable bladder disorders,psoriasis, skin complaints with inflammatory components, chronicinflammatory conditions, inflammatory pain and associated hyperalgesiaand allodynia, neuropathic pain and associated hyperalgesia andallodynia, diabetic neuropathy pain, causalgia, sympatheticallymaintained pain, deafferentation syndromes, asthma, epithelial tissuedamage or dysfunction, herpes simplex, disturbances of visceral motilityat respiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritus, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladderdisorders, comprising the step of administering a compound as describedabove.

Another aspect of the invention relates to a pharmaceutical compositioncomprising a compound according to Claim 1 and apharmaceutically-acceptable diluent or carrier.

Another aspect of the invention relates to the use of a compoundaccording to any of the above embodiments as a medicament.

Another aspect of the invention relates to the use of a compoundaccording to any of the above embodiments in the manufacture of amedicament for the treatment of acute, inflammatory and neuropathicpain, dental pain, general headache, migraine, cluster headache,mixed-vascular and non-vascular syndromes, tension headache, generalinflammation, arthritis, rheumatic diseases, osteoarthritis,inflammatory bowel disorders, anxiety, depression, inflammatory eyedisorders, inflammatory or unstable bladder disorders, psoriasis, skincomplaints with inflammatory components, chronic inflammatoryconditions, inflammatory pain and associated hyperalgesia and allodynia,neuropathic pain and associated hyperalgesia and allodynia, diabeticneuropathy pain, causalgia, sympathetically maintained pain,deafferentation syndromes, asthma, epithelial tissue damage ordysfunction, herpes simplex, disturbances of visceral motility atrespiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritus, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladderdisorders.

Additional Embodiments

The embodiments listed below are presented in numbered form forconvenience and are in addition to the embodiments described above.

1. In a first additional embodiment, the invention proceeds a compoundof Formula I having the structure:

a pharmaceutically-acceptable salt thereof, a tautomer thereof, apharmaceutically-acceptable salt of the tautomer, a stereoisomerthereof, or a mixture thereof, wherein:

m is 0, 1, 2 or 3;

n is 0 or 1;

X¹ is C(R⁴) or N;

X² is CH, CF, or N;

R¹ is C₁₋₆alk or a direct-bonded, C₁₋₂alk-linked, C₁₋₂alkO-linked,saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6- or7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ringcontaining 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, butcontaining no more than one O or S atom, the C₁₋₆alk and ring beingsubstituted by 0, 1, 2 or 3 substituents independently selected fromhalo, oxo, C₁₋₆alk, C₁₋₆alkOH, C₁₋₆alk-C(═O)R^(a), C₁₋₆alk-C(═O)OR^(a),C₁₋₄haloalk, cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a),—SR^(a), ═S, —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(a),—N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(a),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a) and—NR^(a)C₂₋₆alkOR^(a), wherein the ring is additionally substituted by 0or 1 directly bonded, SO₂ linked, C(═O) linked or CH₂ linked saturated,partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-memberedmonocyclic ring containing 0, 1, 2, 3 or 4 heteroatoms selected from N,O and S, but containing no more than one O or S atom, and substituted by0, 1, 2 or 3 groups selected from halo, oxo, C₁₋₆alk, C₁₋₄haloalk,cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a), and —N(R^(a))C(═O)R^(a);

R² is H, halo, cyano, R^(c), —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a) and—NR^(a)C₂₋₆alkOR^(a); or R² is C₁₋₆alk substituted by 0, 1, 2 or 3substituents selected from C₁₋₄haloalk, halo, cyano, nitro, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a) and—NR^(a)C₂₋₆alkOR^(a), or R² is C₁₋₆alk substituted by 0, 1, 2 or 3 halosubstituents and additionally substituted by 0 or 1 substituentsselected from R^(c);

R³ is H, C₁₋₈alk, C₁₋₈alkOH, C₁₋₄haloalk, halo, cyano, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a) or—NR^(a)C₂₋₆alkOR^(a);

R⁴ is independently, at each instance, H, C₁₋₆alk, —C₁₋₃haloalk,—OC₁₋₆alk, —OC₁₋₃haloalk, —N(C₁₋₆alk)C₁₋₆alk, —NHC₁₋₆alk,—NC(═O)C₁₋₆alk, —N(C₁₋₆alk)C₁₋₆alk, F, Cl, Br, CN, OH or NH₂; or R³ andR⁴ together form a four-atom unsaturated bridge containing 0 or 1 Natoms, wherein the bridge is substituted by 0, 1 or 2 R⁵ substituents;

R⁵ is independently, in each instance, halo, OR^(a), CH₃ or CF₃;

R⁶ is F, C₁₋₆alk, or OR^(a);

R^(a) is independently, at each instance, H or R^(b);

R^(b) is independently, at each instance, phenyl, benzyl or C₁₋₆alk, thephenyl, benzyl and C₁₋₆alk being substituted by 0, 1, 2 or 3substituents selected from halo, oxo, C₁₋₄alk, C₁₋₃haloalk, —OC₁₋₄alk,—OH, —NH₂, —OC₁₋₄alk, —OC₁₋₄haloalk, —NHC₁₋₄alk, and —N(C₁₋₄alk)C₁₋₄alk;and

R^(c) is independently, at each instance, a saturated, partiallysaturated or unsaturated 4-, 5- or 6-membered monocyclic ring containing0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein theC₁₋₆alkyl and ring are substituted by 0 or 1 oxo groups substituted by0, 1, 2 or 3 substituents selected from C₁₋₈alk, C₁₋₄haloalk, halo andcyano.

2. The compound of embodiment 1 or the pharmaceutically-acceptable saltthereof, the tautomer thereof, the pharmaceutically-acceptable salt ofthe tautomer, or the mixture thereof, wherein the compound of Formula Ihas the Formula IA:

3. The compound of embodiment 2 or the pharmaceutically-acceptable saltthereof, the tautomer thereof, the pharmaceutically-acceptable salt ofthe tautomer, or the mixture thereof, wherein

X² is selected from CH or N;

R¹ is selected from C₁₋₆alk or a direct-bonded, C₁₋₂alk-linked,C₁₋₂alkO-linked, saturated, partially-saturated or unsaturated 3-, 4-,5-, 6- or 7-membered monocyclic or 7-, 8-, 9-, 10- or 11-memberedbicyclic ring containing 0, 1, 2, 3 or 4 heteroatoms selected from N, Oand S, but containing no more than one O or S atom, the C₁₋₆alk and ringbeing substituted by 0, 1, 2 or 3 substituents independently selectedfrom halo, oxo, C₁₋₆alk, C₁₋₄haloalk, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkNR^(a)R^(a) and —NR^(a)C₂₋₆alkOR^(a), wherein the ring isadditionally substituted by 0 or 1 directly bonded, SO₂ linked, C(═O)linked or CH₂ linked saturated, partially-saturated or unsaturated 3-,4-, 5-, 6- or 7-membered monocyclic ring substituted by 0, 1, 2 or 3groups selected from halo, C₁₋₆alk, C₁₋₄haloalk, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —NR^(a)R^(a), and —N(R^(a))C(═O)R^(a);

R³ is H, C₁₋₈alk, C₁₋₄haloalk, halo, cyano, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a) or—NR^(a)C₂₋₆alkOR^(a); or R³ and R⁴ together form a four-atom unsaturatedbridge containing 0 or 1 N atoms, wherein the bridge is substituted by0, 1 or 2 R⁵ substituents;

R⁵ is independently, in each instance, F, CH₃ or CF₃; and

R⁶ is F.

4. The compound of embodiment 3 or the pharmaceutically-acceptable saltthereof.

5. The compound of embodiment 1 or embodiment 2 or thepharmaceutically-acceptable salt thereof, the tautomer thereof, thepharmaceutically-acceptable salt of the tautomer, or the mixturethereof, wherein R¹ is the saturated, partially-saturated or unsaturated3-, 4-, 5-, 6- or 7-membered monocyclic or 7-, 8-, 9-, 10- or11-membered bicyclic ring and the monocyclic or bicyclic ring issubstituted by 0, 1, 2, or 3 substituents, wherein the substituents areselected from F, Cl, Br, I, oxo, cyano, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—C(H)(CH₃)₂, —CH₂C(H)(CH₃)₂, —CH₂C(H)═CH₂, —CH₂CO₂H, —CH₂CF₃,—C(OH)(CH₃)₂, —SO₂N(H)CH₃, —N(H)SO₂CH₃, —OCH₃, —OCF₃, —OH, —OCH₂CO₂H,—CH₂OH, —CH₂CH₂OH, —CH₂C(H)(CH₃)OH, —CO₂H, —CO₂CH₃, —CO₂CH₂CH₃,—CO₂C(CH₃)₃, —CO₂NH₂, —CO₂N(H)CH₃, —SO₂CH₃, —OC(═O)CH₃, —NH₂,—NHC(═O)CH₃, —N(CH₃)₂, —N(H)CH₂CH₃, —CF₃, —CHF₂, —CH₂C(H)(CF₃)OH,—CH₂C(CH₃)₂OH, —CH₂-phenyl, —C(═O)-phenyl, tetrazolyl, oxadiazolonyl,pyridyl, oxetanyl,

6. The compound of embodiment 1 or embodiment 2 or thepharmaceutically-acceptable salt thereof, the tautomer thereof, thepharmaceutically-acceptable salt of the tautomer, or the mixturethereof, wherein R¹ is a phenyl, pyridyl, pyridinonyl, piperidinonyl,pyridazinonyl, pyrazinonyl, pyridazinyl, pyrimidinyl, pyrazinyl,tetradyrofuranyl, tetrahydropyranyl, thiazolyl, furanyl, thiophenyl,pyrazolyl, isoxazolyl, triazolyl, oxazolyl, imidazolyl, pyrrolidinonyl,piperidinyl, cyclohexyl, cyclohexanonyl, quinolinyl, isoquinolinyl,naphthyridinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, benzothiophenyl,pyrazolopyrimidinyl, triazolopyrimidinyl, indazolyl,tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl,dihydropyrazolooxazinyl, indolinonyl, isoindolinonyl, benzooxazolonyl,oxazolopyridinonyl, benzoimidazolonyl, isoindolindionyl,tetrahydroquinolinyl, dihydroquinolinonyl, benzooxazinonyl,dihydrobenzooxazinonyl, dihydroindenonyl, benzothiazolyl,benzimidazolyl, imidazopyridinyl, tetrazolopyridinyl, quinolinonyl,quinoxalinyl, or quinoxalindionyl substituted by 0, 1, 2, or 3substituents.

7. The compound of embodiment 6 or the pharmaceutically-acceptable saltthereof, the tautomer thereof, the pharmaceutically-acceptable salt ofthe tautomer, or the mixture thereof, wherein R¹ is a phenyl substitutedby 0, or 1 substituent.

8. The compound of embodiment 6 or the pharmaceutically-acceptable saltthereof, the tautomer thereof, the pharmaceutically-acceptable salt ofthe tautomer, or the mixture thereof, wherein R¹ is a pyridinonylsubstituted by 0, or 1 substituent.

9. The compound of embodiment 6 or the pharmaceutically-acceptable saltthereof, the tautomer thereof, the pharmaceutically-acceptable salt ofthe tautomer, or the mixture thereof, wherein R¹ is a pyridylsubstituted by 0, or 1 substituent.

10. The compound of embodiment 6 or the pharmaceutically-acceptable saltthereof, the tautomer thereof, the pharmaceutically-acceptable salt ofthe tautomer, or the mixture thereof, wherein R¹ is a benzooxazolonylsubstituted by 0, or 1 substituent.

11. The compound of embodiment 6 or the pharmaceutically-acceptable saltthereof, the tautomer thereof, the pharmaceutically-acceptable salt ofthe tautomer, or the mixture thereof, wherein R¹ is a quinolinylsubstituted by 0, or 1 substituent.

12. The compound of embodiment 6 or the pharmaceutically-acceptable saltthereof, the tautomer thereof, the pharmaceutically-acceptable salt ofthe tautomer, or the mixture thereof, wherein R¹ is a benzimidazolylsubstituted by 0, or 1 substituent.

13. The compound of embodiment 6 or the pharmaceutically-acceptable saltthereof, the tautomer thereof, the pharmaceutically-acceptable salt ofthe tautomer, or the mixture thereof, wherein R¹ is a group of formula

and the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

14. The compound of embodiment 1 or the pharmaceutically-acceptable saltthereof, the tautomer thereof, the pharmaceutically-acceptable salt ofthe tautomer, or the mixture thereof, wherein R¹ is a group of formula

and the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

15. The compound of embodiment 6 or the pharmaceutically-acceptable saltthereof, the tautomer thereof, the pharmaceutically-acceptable salt ofthe tautomer, or the mixture thereof, wherein R¹ is

and the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

16. The compound of embodiment 6 or the pharmaceutically-acceptable saltthereof, the tautomer thereof, the pharmaceutically-acceptable salt ofthe tautomer, or the mixture thereof, wherein R¹ is

and the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

17. The compound of any one of embodiments 1-3 or 4-16 or thepharmaceutically-acceptable salt thereof, the tautomer thereof, thepharmaceutically-acceptable salt of the tautomer, or the mixturethereof, wherein R⁵ is independently, in each instance, F, Cl, OR^(a),CH₃ or CF₃.

18. The compound of embodiment 17 or the pharmaceutically-acceptablesalt thereof, the tautomer thereof, the pharmaceutically-acceptable saltof the tautomer, or the mixture thereof, wherein R⁵ is F.

19. The compound of any one of embodiments 1-3, or 5-18 or thepharmaceutically-acceptable salt thereof, the tautomer thereof, thepharmaceutically-acceptable salt of the tautomer, or the mixturethereof, wherein R⁶ is F, Me, or OMe.

20. The compound of any one of embodiments 1-3 or 5-19 or thepharmaceutically-acceptable salt thereof, the tautomer thereof, thepharmaceutically-acceptable salt of the tautomer, or the mixturethereof, wherein n is 1.

21. The compound of any one of embodiments 1-3 or 5-20 or thepharmaceutically-acceptable salt thereof, the tautomer thereof, thepharmaceutically-acceptable salt of the tautomer, or the mixturethereof, wherein m is 0 or 1.

22. The compound of embodiment 21 or the pharmaceutically-acceptablesalt thereof, the tautomer thereof, the pharmaceutically-acceptable saltof the tautomer, or the mixture thereof, wherein m is 1.

23. The compound of embodiment 21 or the pharmaceutically-acceptablesalt thereof, the tautomer thereof, the pharmaceutically-acceptable saltof the tautomer, or the mixture thereof, wherein m is 0.

24. The compound of any one of embodiments 1-3 or 5-16 or thepharmaceutically-acceptable salt thereof, the tautomer thereof, thepharmaceutically-acceptable salt of the tautomer, or the mixturethereof, wherein n is 0.

25. The compound of embodiment 24 or the pharmaceutically-acceptablesalt thereof, the tautomer thereof, the pharmaceutically-acceptable saltof the tautomer, or the mixture thereof, wherein R⁶ is F, Me, or OMe.

26. The compound of any one of embodiments 1-3 or 5-25 or thepharmaceutically-acceptable salt thereof, the tautomer thereof, thepharmaceutically-acceptable salt of the tautomer, or the mixturethereof, wherein R² is —H, halo, cyano, —O—C₁-C₆alk, or C₁₋₆alksubstituted by 0, 1, 2 or 3 halo substituents.

27. The compound of embodiment 26 or the pharmaceutically-acceptablesalt thereof, the tautomer thereof, the pharmaceutically-acceptable saltof the tautomer, or the mixture thereof, wherein R² is —H, —F, —Cl, —Br,cyano, —CF₃, —OCH₃, or C₁₋₆alk.

28. The compound of embodiment 26 or the pharmaceutically-acceptablesalt thereof, the tautomer thereof, the pharmaceutically-acceptable saltof the tautomer, or the mixture thereof, wherein R² is —F, —Cl, —Br,cyano, —CF₃, —OCH₃, or C₁₋₆alk.

29. The compound of embodiment 26 or the pharmaceutically-acceptablesalt thereof, the tautomer thereof, the pharmaceutically-acceptable saltof the tautomer, or the mixture thereof, wherein R² is —F.

30. The compound of embodiment 26 or the pharmaceutically-acceptablesalt thereof, the tautomer thereof, the pharmaceutically-acceptable saltof the tautomer, or the mixture thereof, wherein R² is —CF₃.

31. The compound of any one of embodiments 1-3 or 5-25 or thepharmaceutically-acceptable salt thereof, the tautomer thereof, thepharmaceutically-acceptable salt of the tautomer, or the mixturethereof, wherein R² is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —C(CH₃)₃, —CH(CH₃)₂,—CH₂—C(CH₃)₃, —CH═CH₂, —CH₂CH═CH₂, —C≡C—CH₃, or a group of formula

32. The compound of any one of embodiments 1-3, or 5-31 or thepharmaceutically-acceptable salt thereof, the tautomer thereof, thepharmaceutically-acceptable salt of the tautomer, or the mixturethereof, wherein R³ is H, C₁₋₈alk, C₁₋₈alkOH, C₁₋₄haloalk, halo, or—OR^(a).

33. The compound of embodiment 32 or the pharmaceutically-acceptablesalt thereof, the tautomer thereof, the pharmaceutically-acceptable saltof the tautomer, or the mixture thereof, wherein R³ is H, —CH₃, —CH₂CH₃,F, Cl, Br, I, —OCH₃, —OCF₃, —CH(CH₃)OH, or —CF₃.

34. The compound of embodiment 33 or the pharmaceutically-acceptablesalt thereof, the tautomer thereof, the pharmaceutically-acceptable saltof the tautomer, or the mixture thereof, wherein R³ is —CH₃, —CH₂CH₃, F,Cl, I, —OCH₃, —OCF₃, —CH(CH₃)OH, or —CF₃.

35. The compound of embodiment 34 or the pharmaceutically-acceptablesalt thereof, the tautomer thereof, the pharmaceutically-acceptable saltof the tautomer, or the mixture thereof, wherein R³ is —OCF₃ or —CF₃.

36. The compound of embodiment 35 or the pharmaceutically-acceptablesalt thereof, the tautomer thereof, the pharmaceutically-acceptable saltof the tautomer, or the mixture thereof, wherein R³ is —OCF₃.

37. The compound of embodiment 34 or the pharmaceutically-acceptablesalt thereof, the tautomer thereof, the pharmaceutically-acceptable saltof the tautomer, or the mixture thereof, wherein R³ is —CF₃.

38. The compound of embodiment 21 or the pharmaceutically-acceptablesalt thereof, the tautomer thereof, the pharmaceutically-acceptable saltof the tautomer, or the mixture thereof, wherein R³ is —H.

39. The compound of any one of embodiments 1-3, or 5-38 or thepharmaceutically-acceptable salt thereof, the tautomer thereof, thepharmaceutically-acceptable salt of the tautomer, or the mixturethereof, wherein R⁴ is H.

40. The compound of any one of embodiments 1-3, or 5-38 or thepharmaceutically-acceptable salt thereof, the tautomer thereof, thepharmaceutically-acceptable salt of the tautomer, or the mixturethereof, wherein R⁴ is F, Cl, C₁₋₆alk, —OC₁₋₆alk, or —C₁₋₃haloalk.

41. The compound of embodiment 40 or the pharmaceutically-acceptablesalt thereof, the tautomer thereof, the pharmaceutically-acceptable saltof the tautomer, or the mixture thereof, wherein R⁴ is F, Cl, CF₃, CH₃,or OCH₃.

42. The compound of embodiment 41 or the pharmaceutically-acceptablesalt thereof, the tautomer thereof, the pharmaceutically-acceptable saltof the tautomer, or the mixture thereof, wherein R⁴ is F.

43. The compound of any one of embodiments 1-3, or 5-31 or thepharmaceutically-acceptable salt thereof, the tautomer thereof, thepharmaceutically-acceptable salt of the tautomer, or the mixturethereof, wherein R³ and R⁴ together form a four-atom unsaturated bridgecontaining 0 or 1 N atoms, wherein the bridge is substituted by 0, 1 or2 R⁵ substituents.

44. The compound of any one of embodiments 1-3 or 5-43 or thepharmaceutically-acceptable salt thereof, the tautomer thereof, thepharmaceutically-acceptable salt of the tautomer, or the mixturethereof, wherein X² is N.

45. The compound of any one of embodiments 1-3 or 5-43 or thepharmaceutically-acceptable salt thereof, the tautomer thereof, thepharmaceutically-acceptable salt of the tautomer, or the mixturethereof, wherein X² is CH or CF.

46. The compound of embodiment 45 or the pharmaceutically-acceptablesalt thereof, the tautomer thereof, the pharmaceutically-acceptable saltof the tautomer, or the mixture thereof, wherein X² is CH.

47. The compound of embodiment 45 or the pharmaceutically-acceptablesalt thereof, the tautomer thereof, the pharmaceutically-acceptable saltof the tautomer, or the mixture thereof, wherein X² is CF.

48. The compound of any one of embodiments 1-3, or 5-47 or thepharmaceutically-acceptable salt thereof, the tautomer thereof, thepharmaceutically-acceptable salt of the tautomer, or the mixturethereof, wherein X¹ is N.

49. The compound of any one of embodiments 1-3, or 5-47 or thepharmaceutically-acceptable salt thereof, the tautomer thereof, thepharmaceutically-acceptable salt of the tautomer, or the mixturethereof, wherein X¹ is C(R⁴).

50. The compound of embodiment 49 or the pharmaceutically-acceptablesalt thereof, the tautomer thereof, the pharmaceutically-acceptable saltof the tautomer, or the mixture thereof, wherein X¹ is CH.

51. The compound of any one of embodiments 1-3, or 5-43 or thepharmaceutically-acceptable salt thereof, the tautomer thereof, thepharmaceutically-acceptable salt of the tautomer, or the mixturethereof, wherein X¹ is C(R⁴) and X² is N.

52. The compound of any one of embodiments 1-3, or 5-43 or thepharmaceutically-acceptable salt thereof, the tautomer thereof, thepharmaceutically-acceptable salt of the tautomer, or the mixturethereof, wherein X¹ is N and X² is N.

53. The compound of embodiment 1 or the pharmaceutically-acceptable saltthereof, the tautomer thereof, the pharmaceutically-acceptable salt ofthe tautomer, or the mixture thereof, wherein X² is N; R² is F; m is 0;X¹ is CH; R⁴ is For H; R³ is CF₃ or OCF₃; and R¹ is

and the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

54. The compound of embodiment 1, wherein the compound is

-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)-6-oxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxoindoline-5-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide;    or-   (S)—N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-7-carboxamide;    or    the pharmaceutically-acceptable salt thereof, the tautomer thereof,    the pharmaceutically-acceptable salt of the tautomer, or the mixture    thereof.

55. The compound of embodiment 1, wherein the compound is(S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamideor the pharmaceutically-acceptable salt thereof, the tautomer thereof,the pharmaceutically-acceptable salt of the tautomer, or the mixturethereof.

56. The compound of embodiment 1, wherein the compound is(S)-6-oxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-1,6-dihydropyridine-3-carboxamideor the pharmaceutically-acceptable salt thereof, the tautomer thereof,the pharmaceutically-acceptable salt of the tautomer, or the mixturethereof.

57. The compound of embodiment 1, wherein the compound is(S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamideor the pharmaceutically-acceptable salt thereof, the tautomer thereof,the pharmaceutically-acceptable salt of the tautomer, or the mixturethereof.

58. The compound of embodiment 1, wherein the compound is(S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamideor the pharmaceutically-acceptable salt thereof, the tautomer thereof,the pharmaceutically-acceptable salt of the tautomer, or the mixturethereof.

59. The compound of embodiment 1, wherein the compound is(S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxamideor the pharmaceutically-acceptable salt thereof, the tautomer thereof,the pharmaceutically-acceptable salt of the tautomer, or the mixturethereof.

60. The compound of embodiment 1, wherein the compound is(S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxamideor the pharmaceutically-acceptable salt thereof, the tautomer thereof,the pharmaceutically-acceptable salt of the tautomer, or the mixturethereof.

61. The compound of embodiment 1, wherein the compound is(S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxoindoline-5-carboxamideor the pharmaceutically-acceptable salt thereof, the tautomer thereof,the pharmaceutically-acceptable salt of the tautomer, or the mixturethereof.

62. The compound of embodiment 1, wherein the compound is(S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamideor the pharmaceutically-acceptable salt thereof, the tautomer thereof,the pharmaceutically-acceptable salt of the tautomer, or the mixturethereof.

63. The compound of embodiment 1, wherein the compound is(S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamideor the pharmaceutically-acceptable salt thereof, the tautomer thereof,the pharmaceutically-acceptable salt of the tautomer, or the mixturethereof.

64. The compound of embodiment 1, wherein the compound is(S)—N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-7-carboxamideor the pharmaceutically-acceptable salt thereof, the tautomer thereof,the pharmaceutically-acceptable salt of the tautomer, or the mixturethereof.

65. The compound of embodiment 1, wherein the compound is

-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(pyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(2-fluorophenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)-2-oxo-N-(pyridin-2-yl(4-(trifluoromethoxy)phenyl)methyl)-2,3-dihydrobenzo[d]oxazole-5-carboxamide;-   (S)-6-oxo-N-(pyridin-2-yl(4-(trifluoromethoxy)phenyl)methyl)-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((2-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(pyridin-2-yl)methyl)-1Hbenzo[d]imidazole-5-carboxamide;-   (S)-5-fluoro-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethyl)phenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;    or-   (S)-6-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)nicotinic    acid; or    the pharmaceutically-acceptable salt thereof, the tautomer thereof,    the pharmaceutically-acceptable salt of the tautomer, or the mixture    thereof.

66. The compound of embodiment 1, wherein the compound is(S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(pyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamideor the pharmaceutically-acceptable salt thereof, the tautomer thereof,the pharmaceutically-acceptable salt of the tautomer, or the mixturethereof.

67. The compound of embodiment 1, wherein the compound is(S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(2-fluorophenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamideor the pharmaceutically-acceptable salt thereof, the tautomer thereof,the pharmaceutically-acceptable salt of the tautomer, or the mixturethereof.

68. The compound of embodiment 1, wherein the compound is(S)-2-oxo-N-(pyridin-2-yl(4-(trifluoromethoxy)phenyl)methyl)-2,3-dihydrobenzo[d]oxazole-5-carboxamideor the pharmaceutically-acceptable salt thereof, the tautomer thereof,the pharmaceutically-acceptable salt of the tautomer, or the mixturethereof.

69. The compound of embodiment 1, wherein the compound is(S)-6-oxo-N-(pyridin-2-yl(4-(trifluoromethoxy)phenyl)methyl)-1,6-dihydropyridine-3-carboxamideor the pharmaceutically-acceptable salt thereof, the tautomer thereof,the pharmaceutically-acceptable salt of the tautomer, or the mixturethereof.

70. The compound of embodiment 1, wherein the compound is(S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamideor the pharmaceutically-acceptable salt thereof, the tautomer thereof,the pharmaceutically-acceptable salt of the tautomer, or the mixturethereof.

71. The compound of embodiment 1, wherein the compound is(S)—N-((2-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamideor the pharmaceutically-acceptable salt thereof, the tautomer thereof,the pharmaceutically-acceptable salt of the tautomer, or the mixturethereof.

72. The compound of embodiment 1, wherein the compound is(S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(pyridin-2-yl)methyl)-1Hbenzo[d]imidazole-5-carboxamideor the pharmaceutically-acceptable salt thereof, the tautomer thereof,the pharmaceutically-acceptable salt of the tautomer, or the mixturethereof.

73. The compound of embodiment 1, wherein the compound is(S)-5-fluoro-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamideor the pharmaceutically-acceptable salt thereof, the tautomer thereof,the pharmaceutically-acceptable salt of the tautomer, or the mixturethereof.

74. The compound of embodiment 1, wherein the compound is(S)—N-((3-fluoro-4-(trifluoromethyl)phenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamideor the pharmaceutically-acceptable salt thereof, the tautomer thereof,the pharmaceutically-acceptable salt of the tautomer, or the mixturethereof.

75. The compound of embodiment 1, wherein the compound is(S)-6-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)nicotinicacid or the pharmaceutically-acceptable salt thereof, the tautomerthereof, the pharmaceutically-acceptable salt of the tautomer, or themixture thereof.

76. The compound of embodiment 1, wherein the compound is

-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoro-methoxy)-phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoro-methoxy)-phenyl)methyl)-quinoline-7-carboxamide;-   (S)—N-((3,4-dichlorophenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-6-hydro-xynicotinamide;-   (S)—N-((6-chloro-quinolin-3-yl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)quinoline-7-carboxamide;-   (S)—N-((4-(trifluoro-methoxy)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)quinoline-7-carboxamide;-   (S)—N-((4-chloro-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)quinoline-7-carboxamide;-   (S)—N-((8-chloro-quinolin-3-yl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)quinoline-7-carboxamide;-   (S)—N-((7-methoxyquinolin-3-yl)(3-(trifluoro-methyl)pyridin-2-yl)methyl)-quinoline-7-carboxamide;-   (S)—N-((5-chloro-quinolin-3-yl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)quinoline-7-carboxamide;-   (S)—N-((3,4-dichlorophenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-quinoline-7-carboxamide;-   (S)—N-((6-chloro-quinolin-3-yl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-isoquinoline-6-carboxamide;-   (S)—N-(quinolin-3-yl(3-(trifluoro-methyl)pyridin-2-yl)methyl)-quinoline-7-carboxamide;-   (S)—N-((3-chloro-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)quinoline-7-carboxamide;-   (S)—N-(p-tolyl(3-(trifluoromethyl)-pyridin-2-yl)-methyl)quinoline-7-carboxamide;-   (S)—N-(naphthalen-2-yl(3-(trifluoro-methyl)pyridin-2-yl)methyl)-quinoline-7-carboxamide;-   (S)—N-((6-chloro-quinolin-3-yl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-6-hydro-xynicotinamide;-   (S)—N-((3-fluoro-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)quinoline-7-carboxamide;-   (S)—N-((3-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)quinoline-7-carboxamide;-   (S)—N-((4-methoxyphenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-quinoline-7-carboxamide;-   (S)—N-((8-fluoro-quinolin-3-yl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)quinoline-7-carboxamide;-   (S)—N-(m-tolyl(3-(trifluoromethyl)-pyridin-2-yl)-methyl)quinoline-7-carboxamide;-   (S)—N-(quinolin-6-yl(3-(trifluoro-methyl)pyridin-2-yl)methyl)-quinoline-7-carboxamide;-   (S)—N-((8-methoxyquinolin-3-yl)(3-(trifluoro-methyl)pyridin-2-yl)methyl)-quinoline-7-carboxamide;-   (S)—N-((3-methoxyphenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-quinoline-7-carboxamide;-   (S)—N-((3-fluoro-4-methoxyphenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-quinoline-7-carboxamide;-   N-((1S)-(4-(1-hydroxyethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)quinoline-7-carboxamide;-   (S)—N-((4-fluoro-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)quinoline-7-carboxamide;-   (S)—N-((3-methoxypyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)quinoline-7-carboxamide;-   (S)-2-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-nicotinamide;-   (S)-6-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-nicotinamide;-   (S)—N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-pyridazine-3-carboxamide;-   (S)-4-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-picolinamide;-   (S)-6-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-picolinamide;-   (S)-2-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-isonicotinamide;-   N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-6-methoxynicotinamide;-   N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-methoxynicotinamide;-   (S)-6-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-pyridazine-3-carboxamide;-   (S)-5-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-nicotinamide;-   (S)-2-methyl-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-isonicotinamide;-   (S)-6-methyl-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-nicotinamide;-   (S)-6-oxo-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-1,6-dihydropyridine-3-carboxamide;-   (S)-2-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-pyrimidine-5-carboxamide;-   (S)—N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide;-   (S)-2-hydroxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-isonicotinamide;-   (S)—N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-6-methoxynicotinamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-methoxynicotinamide;-   (S)-3-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-isonicotinamide;-   (S)-1-methyl-2-oxo-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-1,2-dihydropyridine-4-carboxamide;-   (S)-1-methyl-6-oxo-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-6-methylnicotinamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-methylisonicotinamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide;-   (S)-4-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-nicotinamide;-   (S)-2-oxo-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)indoline-5-carboxamide;-   (S)-2-methyl-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-pyrimidine-5-carboxamide;-   (S)-5-hydroxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-nicotinamide;-   (S)-2-oxo-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-1,2-dihydropyridine-3-carboxamide;-   (S)-4-methyl-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-pyrimidine-5-carboxamide;-   (S)-4-hydroxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-pyrimidine-5-carboxamide;-   (S)-4-hydroxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-picolinamide;-   (S)-6-oxo-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-1,6-dihydropyridine-2-carboxamide;-   (S)-5-hydroxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-picolinamide;-   6-oxo-N—((S)-(4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-piperidine-3-carboxamide;-   (S)—N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;-   (S)—N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxamide;-   (S)-2-oxo-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)indoline-6-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-oxoindoline-5-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-oxoindoline-6-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-4-(N-methylsulfamoyl)benzamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-oxo-2,3-dihydro-benzo[d]oxazole-5-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-oxo-2,3-dihydro-benzo[d]oxazole-6-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoro-methoxy)-phenyl)methyl)-2-oxo-2,3-dihydro-benzo[d]oxazole-5-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoro-methoxy)-phenyl)methyl)-2-oxo-2,3-dihydro-benzo[d]oxazole-6-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoro-methoxy)-phenyl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide;-   (S)—N-((3-methylpyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)-6-oxo-1,6-dihydro-pyridine-3-carboxamide;-   (S)-1-methyl-N-((3-methylpyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)-6-oxo-1,6-dihydro-pyridine-3-carboxamide;-   (S)—N-((3-methylpyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)-2-oxo-2,3-dihydro-benzo[d]oxazole-5-carboxamide;-   (S)—N-((3-methylpyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-imidazo[1,2-a]pyridine-7-carboxamide;-   (S)—N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-imidazo[1,2-a]pyridine-7-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoro-methoxy)-phenyl)methyl)-imidazo[1,2-a]pyridine-7-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoro-methoxy)-phenyl)methyl)-imidazo[1,2-a]pyridine-6-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoro-methoxy)-phenyl)methyl)-2-oxoindoline-6-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoro-methoxy)-phenyl)methyl)-2-oxoindoline-5-carboxamide;-   (S)-6-oxo-N-((3-(prop-1-yn-1-yl)-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-1,6-dihydro-pyridine-3-carboxamide;-   (S)—N-((3-(prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)quinoline-6-carboxamide;-   (S)-1,3-dioxo-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-isoindoline-5-carboxamide;-   (S)-4-methoxy-N-((3-(prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-benzamide;-   (S)-6-methoxy-N-((3-(prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-nicotinamide;-   (S)—N-((3-(prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)quinoline-7-carboxamide;-   (S)—N-((3-(prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)-benzamide;-   (S)-1,3-dioxo-2-(pyridin-2-yl)-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-isoindoline-5-carboxamide;-   (S)-2-bromo-4-(((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-carbamoyl)-benzoic    acid;-   (S)—N-((3-((3-methyloxetan-3-yl)ethynyl)-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-quinoline-6-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoro-methoxy)-phenyl)(3-fluoro-pyridin-2-yl)-methyl)-6-oxo-1,6-dihydro-pyridine-3-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoro-methoxy)-phenyl)(3-fluoro-pyridin-2-yl)-methyl)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-oxo-1,2-dihydroquinoline-6-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-4-hydro-xyquinoline-7-carboxamide;-   (S)-4-hydroxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-quinoline-7-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-benzamide;-   (S)—N-((3-fluoro-4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-quinoxaline-6-carboxamide;-   (S)-4-hydroxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-quinoline-6-carboxamide;-   (S)-4-chloro-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-quinoline-7-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-pyrazine-2-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-picolinamide;-   (S)-4-chloro-N-((3-fluoropyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)quinoline-6-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-4-hydro-xyquinoline-6-carboxamide;-   (S)—N-((4-ethylphenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)quinoline-7-carboxamide;-   (S)-4-chloro-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-quinoline-6-carboxamide;-   (S)-3-iodo-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-benzamide;-   (S)-2-iodo-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-benzamide;-   (S)—N—((S)-(3-fluoro-4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)tetrahydrofuran-2-carboxamide;-   (S)-4-chloro-N-((3-fluoropyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)quinoline-7-carboxamide;-   (S)-4-(2-hydro-xypropan-2-yl)-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-benzamide;-   (S)-4-iodo-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-benzamide;-   (R)—N—((S)-(3-fluoro-4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)tetrahydrofuran-2-carboxamide;-   (S)—N-((4-fluoro-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-6-methoxynicotinamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-oxo-1,2-dihydroquinoline-7-carboxamide;-   (S)—N-((4-fluoro-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-benzamide;-   (S)-4-isopropyl-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-benzamide;-   (S)—N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-1,8-naphthyridine-2-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-1,8-naphthyridine-2-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-quinoline-6-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-quinoline-7-carboxamide;-   (S)—N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)quinoline-7-carboxamide;-   (S)—N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)quinoline-6-carboxamide;-   (S)-6-amino-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-nicotinamide;-   (S)-6-chloro-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-nicotinamide;-   (S)-2-amino-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-thiazole-4-carboxamide;-   (S)-4-amino-2-methyl-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-pyrimidine-5-carboxamide;-   (S)—N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-thiophene-2-carboxamide;-   (S)-3-amino-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-isonicotinamide;-   (S)-methyl    4-(((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-carbamoyl)-benzoate;-   (S)-4-(1H-tetrazol-5-yl)-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-benzamide;-   tert-butyl    3-(((S)-(4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-carbamoyl)-piperidine-1-carboxylate;-   (S)—N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-1H-pyrazole-4-carboxamide;-   (S)-6-(dimethylamino)-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-nicotinamide;-   (S)-3-amino-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-picolinamide;-   (S)-3-(4-methylthiazol-5-yl)-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-propanamide;-   (S)-6-(ethylamino)-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-nicotinamide;-   (S)-1-methyl-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-1H-imidazole-2-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-methoxypyrimidine-5-carboxamide;-   (S)—N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-pyrimidine-5-carboxamide;-   (S)-6-acetamido-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-nicotinamide;-   (S)-5,7-dimethyl-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-pyrazolo[1,5-a]pyrimidine-2-carboxamide;-   (S)-6-oxo-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-1,6-dihydro-pyridazine-3-carboxamide;-   (S)-5,7-dimethyl-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxamide;-   (S)—N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-tetrahydro-2H-pyran-4-carboxamide;-   (S)-2-(5-methyl-1H-pyrazol-1-yl)-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-acetamide;-   (S)-2-(2-oxooxazolidin-3-yl)-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-acetamide;-   (S)-3-(1H-imidazol-4-yl)-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-propanamide;-   (S)—N-((3-fluoro-4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-2-isobutylquinoline-4-carboxamide;-   2-(tetrahydrofuran-3-yl)-N—((S)-(4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-acetamide;-   (S)-2-(1H-imidazol-4-yl)-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-acetamide;-   (S)-3-amino-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-1H-1,2,4-triazole-5-carboxamide;-   (S)-2-(2-methyl-1H-imidazol-1-yl)-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-acetamide;-   (S)-2-(1H-imidazol-1-yl)-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-acetamide;-   2-acetamido-N—((S)-(4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-propanamide;-   5-oxo-N—((S)-(4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-pyrrolidine-3-carboxamide;-   (S)-2-(2-(trifluoro-methoxy)-phenyl)-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-acetamide;-   (S)-4-hydroxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-1H-indazole-6-carboxamide;-   (S)-4-cyano-N-((3-fluoropyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)-benzamide;-   (S)-3-cyano-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)be;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-methoxybenzamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-quinoxaline-6-carboxamide;-   (S)-4-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-benzamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-4-methoxybenzamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-5-hydro-xypicolinamide;-   (S)-4-(((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-carbamoyl)-phenyl    acetate;-   (S)—N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-1H-indazole-6-carboxamide;-   (S)-2-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-benzamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide;-   (S)—N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-isonicotinamide;-   (S)-3-(((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-carbamoyl)-benzoic    acid;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-benzamide;-   (S)-4-cyano-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-benzamide;-   (S)-5-methyl-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-nicotinamide;-   (S)-4-fluoro-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-benzamide;-   (S)-3-cyano-N-((3-fluoropyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)-benzamide;-   (S)-4-chloro-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-benzamide;-   (S)-3-(dimethylamino)-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-benzamide;-   (S)-3-fluoro-N-((3-fluoropyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)-benzamide;-   (S)—N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-nicotinamide;-   (S)-methyl    3-(((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-carbamoyl)-benzoate;-   (S)-4-methyl-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-oxazole-5-carboxamide;-   (S)-3-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-benzamide;-   (S)-1-methyl-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-1H-pyrazole-3-carboxamide;-   N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-benzamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-picolinamide;-   (S)—N-((3-bromopyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)quinoline-7-carboxamide;-   (S)-4-(dimethylamino)-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-benzamide;-   (S)-2-cyano-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-benzamide;-   (S)-5-bromo-6-chloro-N-((3-fluoropyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)-nicotinamide;-   (S)—N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)furan-3-carboxamide;-   4-cyano-N-((3-fluoropyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)-benzamide;-   (S)-6-oxo-N-(pyridin-2-yl(4-(trifluoromethyl)-phenyl)methyl)-1,6-dihydro-pyridine-3-carboxamide;-   N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-quinoxaline-6-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-nicotinamide;-   N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-quinoline-7-carboxamide;-   (S)-5-bromo-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-picolinamide;-   (S)-6-cyano-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-nicotinamide;-   (S)-3-(((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-carbamoyl)-benzoic    acid;-   (S)-3-chloro-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-benzamide;-   3-fluoro-N-((3-fluoropyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)-benzamide;-   (S)-5-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-picolinamide;-   (S)-3-(trifluoro-methyl)-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-benzamide;-   (S)—N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-pyridazine-4-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-4-(methylsulfonamido)benzamide;-   N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-3-methoxybenz    amide;-   (S)-1-methyl-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-1H-indazole-3-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-3-(methylsulfonyl)-benzamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-4-(methylsulfonyl)-benzamide;-   (S)-2-phenyl-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-acetamide;-   (S)-3-(trifluoro-methoxy)-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-benzamide;-   (S)—N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)isoxazole-5-carboxamide;-   N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-4-methyloxazole-5-carboxamide;-   (S)—N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-benzo[b]thiophene-2-carboxamide;-   3-oxo-N-((S)-(4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-cyclohexanecarboxamide;-   (S)-3-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-propanamide;-   N—((S)-(4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)tetrahydrofuran-3-carboxamide;-   (S)-5-(((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-carbamoyl)-nicotinic    acid;-   (S)-3-fluoro-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-benzamide;-   (S)—N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-picolinamide;-   (S)-tert-butyl    3-(2-oxo-2-(((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)amino)-ethyl)azetidine-1-carboxylate;-   (S)—N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)quinoline-3-carboxamide;-   (S)-4-(trifluoro-methoxy)-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-benzamide;-   N—((S)-(3-((R)-2,2-dimethylcyclopropyl)pyridin-2-yl)-(4-(trifluoro-methyl)phenyl)-methyl)quinoline-7-carboxamide;-   N—((S)-(3-((R)-2,2-dimethylcyclopropyl)pyridin-2-yl)-(4-(trifluoro-methyl)phenyl)-methyl)quinoline-6-carboxamide;-   (S)—N—((S)-(4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)tetrahydrofuran-2-carboxamide;-   (S)—N—((S)-(3-allylpyridin-2-yl)-(4-(trifluoro-methyl)phenyl)-methyl)-2-phenylpropanamide;-   (S)—N-((3-neopentylpyridin-2-yl)(4-(trifluoro-methyl)phenyl)methyl)quinoline-6-carboxamide;-   3,3,3-trifluoro-2-methoxy-2-phenyl-N—((S)-(4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-propanamide;-   (S)-2-(pyridin-3-yl)-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-acetamide;-   (S)—N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-benzo[d]thiazole-6-carboxamide;-   (S)-2-methoxy-2-methyl-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-propanamide;-   (1s,4R)-4-(hydro-xymethyl)-N-((S)-(4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-cyclohexanecarboxamide;-   (S)-4-hydroxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-cyclohexanecarboxamide;-   (S)-2,2-dimethyl-3-oxo-3-(((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)amino)-propanoic    acid;-   (S)-4-(((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-carbamoyl)-cyclohexanecarboxylic    acid;-   (S)-3-oxo-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-2,3-dihydro-1H-indene-5-carboxamide;-   (S)-3-benzoyl-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-benzamide;-   N-((3,4-dichloro-phenyl)(pyridin-2-yl)methyl)-isoquinoline-6-carboxamide;-   (S)—N-((3-chloro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-chloro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxamide;-   (S)—N-((3,4-dichlorophenyl)-(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydro-pyridine-3-carboxamide;-   (S)—N-((3,4-dichlorophenyl)-(3-fluoropyridin-2-yl)methyl)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoro-methoxy)-phenyl)methyl)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxamide;-   (S)—N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-imidazo[1,2-a]pyridine-6-carboxamide;-   (S)—N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-imidazo[1,2-a]pyridine-6-carboxamide;-   (S)-1-ethyl-N-((3-fluoropyridin-2-yl)(4-(trifluoro-methoxy)-phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((2-bromophenyl)(4-(trifluoromethyl)-phenyl)methyl)-quinoline-6-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoro-methyl)phenyl)-(2-(trifluoro-methyl)phenyl)-methyl)quinoline-6-carboxamide;-   (S)—N-((2,6-difluorophenyl)-(4-(trifluoro-methyl)phenyl)-methyl)-6-oxo-1,6-dihydro-pyridine-3-carboxamide;-   (S)—N-((4-(trifluoromethyl)-phenyl)(4-(trifluoromethyl)-pyridin-3-yl)-methyl)quinoline-6-carboxamide;-   (S)-3-oxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)isoindoline-5-carboxamide;-   (S)-2-hydroxy-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)pyrimidine-5-carboxamide;-   (S)-6-oxo-N-((3-propylpyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1,6-dihydropyridine-3-carboxamide;-   (S)-2-allyl-1,3-dioxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)isoindoline-5-carboxamide;-   (S)-1,3-dioxo-2-propyl-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)isoindoline-5-carboxamide;-   (S)-2-methyl-1,3-dioxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)isoindoline-5-carboxamide;-   (S)-1-oxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)isoindoline-5-carboxamide;-   (S)-6-(((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)carbamoyl)nicotinic    acid;-   (S)—N2-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-N5-methylpyridine-2,5-dicarboxamide;-   (S)—N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-1,2,3,4-tetrahydroquinoline-7-carboxamide;-   (S)-5-cyano-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)picolinamide;-   (S)—N-(pyridin-2-yl(4-(trifluoromethyl)phenyl)methyl)-1,2,3,4-tetrahydroquinoline-7-carboxamide;-   (S)-5-cyano-N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-cyanopyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)quinoline-7-carboxamide;-   (S)-2-((6-(((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamoyl)pyridin-3-yl)oxy)acetic    acid;-   (S)-6-(((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamoyl)nicotinic    acid;-   (S)-6-(((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)nicotinic    acid;-   (S)—N2-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)pyridine-2,5-dicarboxamide;-   (S)-4-(((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)benzoic    acid;-   (S)-3-(pyridin-2-yl)-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)propanamide;-   (S)-5-(((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)picolinic    acid; or-   (S)—N-((3-(tert-butyl)pyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)quinoline-7-carboxamide;    or    the pharmaceutically-acceptable salt thereof, the tautomer thereof,    the pharmaceutically-acceptable salt of the tautomer, or the mixture    thereof.

77. The compound of embodiment 1, wherein the compound is

-   (R)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-2-(pyridin-2-yl)acetamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-2-(pyridin-3-yl)acetamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-2-(pyridin-4-yl)acetamide;-   (S)—N-((3,6-difluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(5-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(pyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(pyridin-2-yl)methyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(2-fluorophenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(2-fluorophenyl)methyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   N—((S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-1-((S)-2-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   N—((S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-1-((R)-2-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   N—((S)-(3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1-(S)-2-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   N—((S)-(3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1-(R)-2-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-1-(2-hydroxy-2-methylpropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1-(2-hydroxy-2-methylpropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-1-(oxetan-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1-(oxetan-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-(phenyl(3-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-7-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)tetrazolo[1,5-a]pyridine-6-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)tetrazolo[1,5-a]pyridine-7-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)tetrazolo[1,5-a]pyridine-6-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)tetrazolo[1,5-a]pyridine-7-carboxamide;-   (S)—N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)tetrazolo[1,5-a]pyridine-6-carboxamide;-   (S)—N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)tetrazolo[1,5-a]pyridine-7-carboxamide;-   (S)—N-((3-methylpyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxamide;-   (S)—N-((3-methylpyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)imidazo[1,2-a]pyridine-6-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-4-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)benzamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-4-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)benzamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-5-oxo-4,5-dihydropyrazine-2-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide;-   (S)—N-((3-methylpyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-4-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)benzamide;-   (S)—N-((3,5-dimethylphenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-5-methylphenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-5-methylphenyl)(3-fluoropyridin-2-yl)methyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-5-(trifluoromethyl)phenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-5-(trifluoromethyl)phenyl)(3-fluoropyridin-2-yl)methyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3,5-difluorophenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3,5-difluorophenyl)(3-fluoropyridin-2-yl)methyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3,4-difluorophenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3,4-difluorophenyl)(3-fluoropyridin-2-yl)methyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(3-methyl-5-(trifluoromethyl)phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-4-methylphenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-4-methylphenyl)(3-fluoropyridin-2-yl)methyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-4-methoxyphenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-4-methoxyphenyl)(3-fluoropyridin-2-yl)methyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((4-fluoro-3-methylphenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((4-fluoro-3-methylphenyl)(3-fluoropyridin-2-yl)methyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((4-fluorophenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((4-fluorophenyl)(3-fluoropyridin-2-yl)methyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-methoxyphenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-methoxyphenyl)methyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((4-chloro-3-fluorophenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((4-chloro-3-fluorophenyl)(3-fluoropyridin-2-yl)methyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-2-oxoindoline-5-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-methylpyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-methylpyridin-2-yl)methyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-oxo-4,5-dihydropyrazine-2-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-5-oxo-4,5-dihydropyrazine-2-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-methylpyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-methylpyridin-2-yl)methyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxamide;-   (S)—N-((3-methylpyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)-1-methyl-N-((3-methylpyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)-2-oxo-N-(pyridin-2-yl(4-(trifluoromethyl)phenyl)methyl)-2,3-dihydrobenzo[d]oxazole-5-carboxamide;-   (S)-2-oxo-N-(pyridin-2-yl(4-(trifluoromethoxy)phenyl)methyl)-2,3-dihydrobenzo[d]oxazole-5-carboxamide;-   (S)-6-oxo-N-((4-(trifluoromethyl)phenyl)(3-vinylpyridin-2-yl)methyl)-1,6-dihydropyridine-3-carboxamide;-   (S)-1-ethyl-N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3,4-dichlorophenyl)(3-fluoropyridin-2-yl)methyl)-1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)-1-ethyl-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1-isopropyl-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)-5-bromo-N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1-methoxy-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)-1-benzyl-N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-5-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)thiophene-2-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)thiophene-2-carboxamide;-   N-((4-iodophenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)-6-oxo-N-(pyridin-2-yl(4-(trifluoromethoxy)phenyl)methyl)-1,6-dihydropyridine-3-carboxamide;-   (S)-1-methyl-6-oxo-N-(pyridin-2-yl(4-(trifluoromethoxy)phenyl)methyl)-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(p-tolyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3,4-dimethylphenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(3-methyl-4-(trifluoromethoxy)phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-bromopyridin-2-yl)(3-fluoro-4-(trifluoromethoxy)phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-bromopyridin-2-yl)(3-fluoro-4-(trifluoromethoxy)phenyl)methyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxamide;-   (S)—N-((2-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide    2,2,2-trifluoroacetate;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-1-methyl-1H-imidazole-2-carboxamide    2,2,2-trifluoroacetate;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-4-methyl-1H-imidazole-2-carboxamide    2,2,2-trifluoroacetate;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-hydroxypicolinamide    2,2,2-trifluoroacetate;-   (S)-4-acetamido-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-3-hydroxybenzamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(pyridin-2-yl)methyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1H-benzo[d]imidazole-5-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(pyridin-2-yl)methyl)-1H-benzo[d]imidazole-5-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1-methyl-1H-benzo[d]imidazole-6-carboxamide;-   (S)-1-(difluoromethyl)-N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-2-methyl-1H-benzo[d]imidazole-5-carboxamide;-   (S)-methyl    6-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)nicotinate;-   (S)-1-(difluoromethyl)-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)-5-fluoro-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)-5-chloro-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-methoxy-6-oxo-1,6-dihydropyridine-2-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethyl)phenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)-methyl    6-(((3-fluoro-4-(trifluoromethoxy)phenyl)(pyridin-2-yl)methyl)carbamoyl)nicotinate;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-1-((1-hydroxycyclopropyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   N—((S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1-((S)-3,3,3-trifluoro-2-hydroxypropyl)-1,6-dihydropyridine-3-carboxamide;-   N—((S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1-((R)-3,3,3-trifluoro-2-hydroxypropyl)-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-6-methylpyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   N-((3-fluoro-4-(trifluoromethoxy)phenyl)(4-fluorophenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   N-((2,3-difluorophenyl)(3-fluoro-4-(trifluoromethoxy)phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   N-((2,4-difluorophenyl)(3-fluoro-4-(trifluoromethoxy)phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   N-((2,5-difluorophenyl)(3-fluoro-4-(trifluoromethoxy)phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)-6-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)picolinic    acid trifluoroacetate;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide;-   N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluorophenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   N-((2,6-difluorophenyl)(3-fluoro-4-(trifluoromethoxy)phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (R)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   N-((3-fluoro-4-(trifluoromethoxy)phenyl)(6-methoxypyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   N-((3-fluoro-4-(trifluoromethoxy)phenyl)(5-methoxypyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   N-((3-fluoro-4-(trifluoromethoxy)phenyl)(4-methoxypyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   N-((3-fluoro-4-(trifluoromethoxy)phenyl)(4-methylpyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   N-((3-fluoro-4-(trifluoromethoxy)phenyl)(5-methylpyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-2-oxo-2,3-dihydrooxazolo[4,5-b]pyridine-5-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-2-oxo-1,2-dihydrooxazolo[5,4-b]pyridine-5-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-2-oxo-2,3-dihydrooxazolo[4,5-b]pyridine-6-carboxamide;-   (S)-2-(5-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)-2-oxopyridin-1(2H)-yl)acetic    acid;-   (S)-2-(5-(((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamoyl)-2-oxopyridin-1(2H)-yl)acetic    acid;-   (S)—N-((3-ethylpyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;-   (S)-2-amino-4-(((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamoyl)phenyl    acetate;-   (S)-4-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)benzoic    acid;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)imidazo[1,2-a]pyridine-6-carboxamide;-   (S)-6-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)nicotinic    acid;-   (R)-6-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)nicotinic    acid;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-1-hydroxy-4-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxamide;-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-2-oxo-1,2-dihydrooxazolo[5,4-c]pyridine-6-carboxamide;    or-   (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-2-oxo-2,3-dihydrooxazolo[4,5-c]pyridine-6-carboxamide;    or    the pharmaceutically-acceptable salt thereof, the tautomer thereof,    the pharmaceutically-acceptable salt of the tautomer, or the mixture    thereof.

78. The compound or tautomer of any one of embodiments 1-3 or 5-77 in aneutral form.

79. The compound of any one of embodiments 1-3 or 5-77 in a neutralform.

80. The pharmaceutically-acceptably salt of the compound or thepharmaceutically acceptable salt of the tautomer of any one ofembodiments 1-3 or 5-77.

81. The pharmaceutically-acceptably salt of the compound of any one ofembodiments 1-3 or 5-77.

82. A pharmaceutical composition comprising the compound according toany one of embodiments 1-3 or 5-77 or the pharmaceutically-acceptablesalt thereof, the tautomer thereof, the pharmaceutically-acceptable saltof the tautomer, or the mixture thereof, and apharmaceutically-acceptable diluent or carrier.

83. A method of treating acute, inflammatory and neuropathic pain,dental pain, general headache, migraine, cluster headache,mixed-vascular and non-vascular syndromes, tension headache, generalinflammation, arthritis, rheumatic diseases, osteoarthritis,inflammatory bowel disorders, depression, anxiety, inflammatory eyedisorders, inflammatory or unstable bladder disorders, psoriasis, skincomplaints with inflammatory components, chronic inflammatoryconditions, inflammatory pain and associated hyperalgesia and allodynia,neuropathic pain and associated hyperalgesia and allodynia, diabeticneuropathy pain, causalgia, sympathetically maintained pain,deafferentation syndromes, asthma, epithelial tissue damage ordysfunction, herpes simplex, disturbances of visceral motility atrespiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritus, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladder disordersin a subject, the method comprising administering the compound accordingto any one of embodiments 1-3 or 5-77 or the pharmaceutically-acceptablesalt thereof, the tautomer thereof, the pharmaceutically-acceptable saltof the tautomer, or the mixture thereof to the subject.

84. The method of embodiment 83, wherein the subject is suffering fromneuropathic pain.

85. The method of embodiment 83, wherein the subject is suffering frommigraine pain.

86. The use of the compound according to any one of embodiments 1-3 or5-77 or the pharmaceutically-acceptable salt thereof, the tautomerthereof, the pharmaceutically-acceptable salt of the tautomer, or themixture thereof in the preparation of a medicament.

87. The use of the compound according to any one of embodiments 1-3 or5-77 or the pharmaceutically-acceptable salt thereof, the tautomerthereof, the pharmaceutically-acceptable salt of the tautomer, or themixture thereof for treating acute, inflammatory and neuropathic pain,dental pain, general headache, migraine, cluster headache,mixed-vascular and non-vascular syndromes, tension headache, generalinflammation, arthritis, rheumatic diseases, osteoarthritis,inflammatory bowel disorders, depression, anxiety, inflammatory eyedisorders, inflammatory or unstable bladder disorders, psoriasis, skincomplaints with inflammatory components, chronic inflammatoryconditions, inflammatory pain and associated hyperalgesia and allodynia,neuropathic pain and associated hyperalgesia and allodynia, diabeticneuropathy pain, causalgia, sympathetically maintained pain,deafferentation syndromes, asthma, epithelial tissue damage ordysfunction, herpes simplex, disturbances of visceral motility atrespiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritus, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladder disordersin a subject.

88. The use of embodiment 87, wherein the use is for treatingneuropathic pain.

89. The use of embodiment 87, wherein the use is for treating migraine.

90. The compound according to any one of embodiments 1-3 or 5-71 or thepharmaceutically-acceptable salt thereof, the tautomer thereof, thepharmaceutically-acceptable salt of the tautomer, or the mixture thereoffor treating acute, inflammatory and neuropathic pain, dental pain,general headache, migraine, cluster headache, mixed-vascular andnon-vascular syndromes, tension headache, general inflammation,arthritis, rheumatic diseases, osteoarthritis, inflammatory boweldisorders, depression, anxiety, inflammatory eye disorders, inflammatoryor unstable bladder disorders, psoriasis, skin complaints withinflammatory components, chronic inflammatory conditions, inflammatorypain and associated hyperalgesia and allodynia, neuropathic pain andassociated hyperalgesia and allodynia, diabetic neuropathy pain,causalgia, sympathetically maintained pain, deafferentation syndromes,asthma, epithelial tissue damage or dysfunction, herpes simplex,disturbances of visceral motility at respiratory, genitourinary,gastrointestinal or vascular regions, wounds, burns, allergic skinreactions, pruritus, vitiligo, general gastrointestinal disorders,gastric ulceration, duodenal ulcers, diarrhea, gastric lesions inducedby necrotising agents, hair growth, vasomotor or allergic rhinitis,bronchial disorders or bladder disorders in a subject.

91. The compound of embodiment 90 or the pharmaceutically-acceptablesalt thereof, the tautomer thereof, the pharmaceutically-acceptable saltof the tautomer, or the mixture thereof for treating neuropathic pain ina subject.

92. The compound of embodiment 90 or the pharmaceutically-acceptablesalt thereof, the tautomer thereof, the pharmaceutically-acceptable saltof the tautomer, or the mixture thereof for treating migraine in asubject.

EXAMPLES

Unless otherwise noted, all materials were obtained from commercialsuppliers and used without further purification. All parts are by weightand temperatures are in degrees centigrade unless otherwise indicated.All microwave assisted reactions were conducted with a Smith Synthesizerfrom Biotage. Mass spectral data was determined by electrosprayionization technique. All examples were purified to >90% purity asdetermined by high-performance liquid chromatography. Unless otherwisestated, reactions were run at room temperature.

The following abbreviations are used:

AcOH- Acetic acid DABCO- 1,4-Diazabicyclo[2.2.2]octane DCM-Dichloromethane DIPEA- Diisopropyl ethylamine DMSO- Dimethyl sulfoxideDMF- N,N-dimethylformamide THF- Tetrahydrofuran EDCI-1-Ethy1-3-(3-dimethylaminopropyl) carbodiimide Et₂O- Diethyl etherEtOAc- Ethyl acetate EtOH- Ethyl alcohol HATU-2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3- tetramethyluroniumhexafluorophosphate MeCN- Acetonitrile MeOH- Methyl alcohol n-BuLi-n-Butyllithium NMP- N-Methyl-2-pyrrolidinone also known as1-methyl-2-pyrrolidinone SFC- Supercritical fluid chromatography TEA-Triethylamine TFA- Trifluoroacetic acid TLC- Thin Layer ChromatographypTSA- para-Toluenesulfonic acid h- Hour min- Minute rt- Toom temperature(22-25° C.) mL Milliliters μL Microliters g Grams μg Micrograms mgMilligrams μmoL Micromolars

General Method of Preparation

The compounds described herein are prepared using techniques known toone skilled in the art through the reaction sequences depicted inschemes 1-4 as well as by other methods. Furthermore, in the followingschemes, where specific acids, bases, reagents, coupling agents,solvents, etc. are mentioned, it is understood that other suitableacids, bases, reagents, coupling agents, solvents, etc. may be used andare included within the scope of the present invention.

Diarylamines used for the synthesis of compounds of the presentinvention were prepared as described in Scheme 1. 2-Formylpyridines ofthe Formula (1) were treated with 2-methylpropane-2-sulfinamide andcopper sulfate in DCM to give2-methyl-N-(pyridin-2-ylmethylene)propane-2-sulfinamides of the Formula(2a). The compounds of Formula (2a) were treated with aryl or heteroarylmetal halides of Formula (3) at low temperature to give sulfinamides ofthe Formula (4). Hydrolysis of sulfinamides (4) with hydrochloric acidin MeOH gives diaryl amines of Formula (5a).

An alternative approach to diaryl amines of Formula (5a) is shown inScheme 2. Aryl or heteroaryl aldehydes of the Formula (6) were treatedwith 2-methylpropane-2-sulfinamide and copper sulfate in DCM to givesulfinimines of the Formula (7). The compounds of Formula (7) weretreated with aryl or heteroaryl metal halides of Formula (8) at lowtemperature to give sulfinamides of the Formula (4). Hydrolysis ofsulfinamides (4) with hydrochloric acid in MeOH gives diaryl amines ofFormula (5a).

The methods described in Scheme 1-2 can be adapted to a asymmetricsyntheses using the appropriate (R)- or(S)-2-methylpropane-2-sulfinamides to give sulfinimines of the Formula(2b) or (2c). Subsequent aryl metal addition and hydrolysis gave chiralamines of Formula (5b) or (5c).

The coupling reaction of diarylamines of Formula (5a-c) with the variouscarboxylic acids of Formula (9) can be performed as shown in Scheme 4.The coupling reaction can be mediated by a suitable coupling agent suchas HATU in the presence of a base in a suitable solvent to affordcompounds of the present invention (Formula (I)).

Experimentals for Intermediates

Intermediate 1:(S)-(4-(Trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methanamineHydrochloride

Step 1.(S,E)-2-Methyl-N-((3-(trifluoromethyl)pyridin-2-yl)methylene)-propane-2-sulfinamide

To a solution of 3-(trifluoromethyl)picolinaldehyde (FrontierScientific, 9.80 g, 56.0 mmol) and DCM (50 mL) was added(S)-2-methylpropane-2-sulfinamide (AK Scientific, 10.3 g, 85.0 mmol) andcopper(II) sulfate (35.3 g, 221 mmol). After 1.5 h at rt, the reactionwas filtered through a pad of Celite® brand filter agent and rinsed withDCM. The filtrate was concentrated in vacuo to give a dark green oil.The oil thus obtained was loaded onto a silica gel column and elutedwith 30% EtOAc in hexanes to give(S,E)-2-methyl-N-((3-(trifluoro-methyl)pyridin-2-yl)methylene)propane-2-sulfinamide,as a golden oil. ¹H NMR (δ ppm, CDCl₃, 300 MHz): 9.02 (d, J=4.3 Hz, 1H),8.70 (d, J=1.3 Hz, 1H), 8.38 (d, J=7.7 Hz, 1H), 7.79 (dd, J=7.9 & 4.8Hz, 1H), 1.18 (s, 9H). MS (ESI pos. ion) m/z: 279.1 (M+H).

Step 2.(S)-2-Methyl-N—((S)-(4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)-pyridin-2-yl)methyl)propane-2-sulfinamide

To an oven-dried flask containing magnesium (3.46 g, 143 mmol) and Et₂O(120 mL) was added diisobutylaluminum hydride (0.950 mL, 0.950 mmol) and1 mL of 1-bromo-4-(trifluoromethyl)benzene (12.5 mL, 91 mmol) dropwise.The solution was stirred for ˜20 min, during which time the reactionwent from clear to a brownish tint. The reaction was placed in an icebath and the remaining 1-bromo-4-(trifluoromethyl)benzene was addeddropwise over 20 minutes. In a separate flask, a solution of(S,E)-2-methyl-N-((3-(trifluoromethyl)pyridin-2-yl)-methylene)propane-2-sulfinamide(13.22 g, 47.5 mmol) and THF (80 mL) was cooled to −78° C. for 10 minand the Grignard solution was added over 30 min. After 1 h, the reactionwas quenched with saturated aqueous potassium sodium tartrate (10 mL).The reaction was then poured into H₂O (150 mL). The entire solution wasfiltered through a pad of Celite® brand filter agent and rinsed with THFand EtOAc. The resulting filtrate was separated and the organicsconcentrated in vacuo to give the product as a dark orange oil. The oilthus obtained was adsorbed onto a plug of silica gel and chromatographedthrough a Redi-Sep® pre-packed silica gel column (120 g), eluting with0% to 40% EtOAc in hexanes, to provide(S)-2-methyl-N-((S)-(4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)propane-2-sulfinamideas a golden oil. ¹H NMR (δ ppm, DMSO-d₆, 600 MHz): δ 8.93 (d, J=4.8 Hz,1H), 7.25 (d, J=7.8 Hz, 1H), 7.71-7.67 (m, 2H), 7.61-7.59 (m, 1H), 7.54(d, J=8.4 Hz, 2H), 6.08 (d, J=9 Hz, 1H), 5.90 (d, J=9 Hz, 1H), 1.20 (s,9H). MS (ESI pos. ion) m/z: 425.1 (M+H).

Step 3.(S)-(4-(Trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)-methanamineHydrochloride

To a cooled (0° C.) stirring solution of((S)-2-methyl-N—((S)-(4-(trifluoro-methyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)propane-2-sulfonamide(27 g, 63 mmol) in Et₂O (270 mL) was added 4.0 M HCl in 1,4-dioxane (157mL, 630 mmol, 10 equiv.) at 0° C., and the reaction mixture was stirredfor 30 min at the same temperature. The reaction progress was monitoredby TLC (50% EtOAc in petroleum ether). After completion of the reaction,the reaction mixture was concentrated under reduced pressure andtriturated with Et₂O to get a white solid which was filtered and driedto give(S)-(4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methanaminehydrochloride as a white solid. (δ ppm, DMSO-d₆, 600 MHz): δ 9.26 (s,3H), 9.08 (d, J=4.2 Hz, 1H), 8.35 (d, J=7.8 Hz, 1H), 7.82-7.77 (m, 3H),7.67 (d, J=8.4 Hz, 2H), 5.94 (s, 1H). MS (ESI pos. ion) m/z: 321.1 (M+H)for free base.

Intermediate 2:(S)-(4-(Trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methanamineHydrochloride

Step 1. 3-Fluoropicolinaldehyde

To a stirred solution of DABCO (262.4 g, 2342 mmol) in anhydrous Et₂O(2.1 L) at −25° C. in a 10 L 3-neck round bottom flask was added n-BuLi(2.5 M in hexane, 938 mL, 2342 mmol). The mixture was stirred between−25° C. to −10° C. for 45 min. and then cooled to −70° C. To the abovesolution was added 3-fluoropyridine (206.7 g, 2129 mmol) dropwise, andthe reaction was stirred between −70° C. to −60° C. for 1.5 h before DMF(344 mL, 4258 mmol) was added. The progress of the reaction wasmonitored by TLC (5% EtOAc in Petroleum ether). After 1 h stirring at−70° C., water (800 mL) was added, and the reaction was allowed to warmto rt. The layers were separated, and the aqueous layer was extractedwith DCM (5×1 L). The combined organic layers were washed with brine anddried over sodium sulfate. After removal of solvent the initiallyobtained product was purified by silica gel chromatography using agradient of EtOAc in hexane to give the title compound as pale yellowoil. ¹H-NMR (400 MHz, CDCl₃): δ ppm 10.21 (s, 1H), 8.63 (t, J=2.2 Hz,1H), 7.54-7.57 (m, 2H). MS (ESI pos. ion) m/z: 126.0 (M+H).

Step 2.(S,E)-N-((3-Fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide

A mixture of 3-fluoropicolinaldehyde (300 g, 2400 mmol), copper sulfate(572 g, 3600 mmol) and (S)-2-methylpropane-2-sulfinamide (319 g, 2640mmol) in DCM (3 L) in a 10 L 3-neck round bottom flask was stirred for 3h at rt. The progress of the reaction was monitored by TLC (30% EtOAc inpetroleum ether). After completion of reaction, the solid was filteredoff and the filtrate was concentrated under vacuum. The initiallyobtained product was purified by column chromatography using silica(60-120 mesh) with 20% EtOAc in n-hexane as eluent to give the titlecompound sulfinamide as yellow oil. ¹H-NMR (400 MHz, CDCl₃): δ ppm 8.89(s, 1H), 8.64 (s, 1H), 7.55 (t, J=8.4 Hz, 1H), 7.46 (d, J=3.6 Hz, 1H),1.29 (s, 9H). MS (ESI pos. ion) m/z: 155.0 (M-O and t-Bu).

Step-3.(S)—N—((S)-(3-Fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-2-methylpropane-2-sulfinamide

To a stirred suspension of magnesium (170 g, 2365 mmol) in THF (1.35 L),was added 4-bromobenzotrifluoride (532 g, 2365 mmol). Stirring wascontinued for 4 h (caution: slightly exothermic, cooled with a waterbath if needed). The solution was cannulated to a stirred solution of(S,E)-N-((3-fluoro-pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide(270 g, 1182 mmol) in THF (1.3 L) at −78° C. dropwise. Stirring wascontinued for 1 h. The progress of the reaction was monitored by TLC(50% EtOAc in petroleum ether). After completion of the reaction, thereaction mixture was quenched with saturated aqueous NH₄Cl (2.5 L), andthe solution was extracted with Et₂O (5×500 mL). The organic layers werecombined, dried over Na₂SO₄, concentrated, and purified by columnchromatography using silica (100-200 mesh) with 25-30% EtOAc inpetroleum ether as eluent to give the title compound as a brown oil.¹H-NMR (400 MHz, CDCl₃): δ ppm 8.45 (d, J=3.6 Hz, 1H), 7.73-7.78 (m,1H), 7.71 (d, J=8.4 Hz, 2H), 7.63 (m, 2H), 7.43-7.48 (m, 1H), 6.23 (d,J=6.8 Hz, 1H), 5.99 (d, J=6.8 Hz, 1H), 1.36 (s, 9H). MS (ESI pos. ion)m/z: 375.1 (M-O and t-Bu).

Step 4. (S)-(3-Fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamineHydrochloride

To a cooled (0° C.) stirring solution of(S)—N—((S)-(3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-2-methylpropane-2-sulfinamide(108 g, 288.8 mmol) in DCM:EtOH (1:1, 1080 mL), was added saturated HClin 1,4-dioxane (216 mL). Stirring was continued for 2 h at 0° C. Theprogress of the reaction was monitored by TLC (100% EtOAc). Aftercompletion of the reaction, the reaction mixture was concentrated andtriturated with Et₂O to give a white solid which was filtered and driedto give the title compound as a white solid. ¹H-NMR (400 MHz, CDCl₃) δppm 9.23 (s, 3H), 8.60 (d, J=4.8 Hz, 1H), 7.87 (d, J=1.2 Hz, 1H), 7.84(d, J=8.4 Hz, 2H), 7.72 (d, J=8.4 Hz, 2H), 7.59-7.63 (m, 1H), 6.09 (s,1H). MS (ESI pos. ion) m/z: 270.1 (M+H).

Intermediate 2a:(4-(Trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methanamineHydrochloride

Following the procedure detailed above for Intermediate 2, but replacing(S)-2-methylpropane-2-sulfinamide with racemic2-methylpropane-2-sulfinamide in STEP 2 gave the title compound as awhite solid.

General Procedure for Preparation of Diarylmethanamines (Intermediates3-41)

Additional diarylmethanamies were prepared as described in Scheme 5,Steps 2-3 or Scheme 6, Steps 3-4; substituting the appropriate startingmaterials. Variations in methods applied in Step 2 of the variousintermediate syntheses are elaborated below.

Method A:

Intermediate 3:(S)—N—((S)-(4-Methoxyphenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide

Magnesium metal (0.095 g, 3.91 mmol) was activated using a crystal ofiodine prior to addition of THF (1 mL). 1-Bromo-4-methoxybenzene (0.400g, 2.139 mmol) was added, and the reaction was left without stirring for5 minutes after which initiation was observed. Additional THF (15 mL)was added and the mixture was stirred for 2 hours.(S,E)-2-Methyl-N-((3-(trifluoromethyl)pyridin-2-yl)methylene)propane-2-sulfinamide(0.500 g, 1.797 mmol) was added, and the mixture was stirred for 10minutes. The reaction was quenched by addition of saturated aqueousNH₄Cl (10 mL). H₂O (100 mL) and EtOAc (150 mL) were added, and thephases mixed and separated. The organic layer was dried with MgSO₄ andevaporated to dryness under reduced pressure. Purification using silicachromatography (hexane to EtOAc gradient) gave(S)—N—((S)-(4-methoxyphenyl)-(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide.

The sulfinamide above was then subjected to the hydrolysis conditionssimilar to those described above in Scheme 5, Step 3 to giveIntermediate 3 in Table 1 below.

Method B:

Intermediate 4:(S)—N—((S)-(3,4-Dichlorophenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide

(S,E)-2-Methyl-N-((3-(trifluoromethyl)pyridin-2-yl)methylene)propane-2-sulfinamide(0.493 g, 1.772 mmol) was dissolved in dry THF (10 mL) and cooled in anice bath. 3,4-Dichlorophenylmagnesium bromide (Aldrich, 0.5 M solutionin THF, 4.0 mL, 2.0 mmol) was added, and the reaction was stirred for 5minutes. Saturated aqueous NH₄Cl (10 mL), H₂O (100 mL) and EtOAc (100mL) were added and the phases were mixed and separated. The organiclayer was dried with MgSO₄ and evaporated to dryness under reducedpressure. Purification using silica chromatography (hexane to EtOAcgradient) gave(S)—N—((S)-(3,4-dichloro-phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide.

The sulfinamide above was then subjected to the hydrolysis conditionssimilar to those described above in Scheme 5, Step 3 to giveIntermediate 4 in Table 1 below.

Method C:

Intermediate 5:(S)—N—((S)-(3-Fluoropyridin-2-yl)(4-(trifluoromethoxy)-phenyl)methyl)-2-methylpropane-2-sulfinamide

1-Iodo-4-(trifluoromethoxy)benzene (1.00 g, 3.47 mmol) was dissolved indry THF (10 mL) and cooled in an ice bath. Isopropylmagnesium chloride,lithium chloride complex (14% solution in THF, Aldrich, 3.07 mL, 2.82mmol) was added, and the mixture was stirred for 10 min. A solution of(S,E)-N-((3-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide(0.643 g, 2.82 mmol) in dry THF (10 mL) was added and the reaction wasstirred. After 50 minutes, the reaction was quenched by addition ofsaturated aqueous NH₄Cl (10 mL). H₂O (100 mL) and EtOAc (150 mL) wereadded, and the phases were mixed and separated. The organic layer wasdried with MgSO₄ and evaporated to dryness under reduced pressure.Purification using silica chromatography (hexane to EtOAc gradient) gavethe desired(S)—N—((S)-(3-fluoropyridin-2-yl)(4-(trifluoro-methoxy)phenyl)methyl)-2-methylpropane-2-sulfinamide.

The sulfinamide was then subjected to the hydrolysis conditions similarto those described above in Scheme 6, Step 4 to give Intermediate 5 inTable 1 below.

TABLE 1 Additional diarylmethanamines prepared analogous to Scheme 5 and6 (Intermediates 3-41). Unless otherwise stated, all amines in thistable are hydrochloride salts. Aryl Halide Mol. Inter- or GrignardFormula mediate Method in Step 2 Structure Name (Mol. Wt.) 3   A

(S)-(4- methoxyphenyl)- (3-(trifluoro- methyl)- pyridin-2-yl)-methanamine C₁₄H₁₃F₃N₂O (282.26) 4   B

(S)-(3,4- dichloro- phenyl)(3- (trifluoro- methyl)- pyridin-2-yl)-methanamine C₁₃H₉Cl₂F₃N₂ (321.13) 5   C

(S)-(4- (trifluoro- methoxy)- phenyl)(3- (trifluoro- methyl)-pyridin-2-yl)- methanamine C₁₄H₁₀F₆N₂O (336.23) 6   A

(S)-(3-fluoro- 4-(trifluoro- methoxy)- phenyl)(3- fluoropyridin- 2-yl)-methanamine C₁₃H₉F₅N₂O (304.22) 6b² A

(3-fluoro-4- (trifluoro- methoxy)- phenyl)(3- fluoropyridin- 2-yl)-methanamine C₁₃H₉F₅N₂O (304.22) 7   A

(S)-(3-fluoro- 4-(trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin-2-yl)- methanamine C₁₄H₉F₇N₂ (338.22) 8   C

(S)-(3-fluoro- pyridin-2-yl)- (4-(trifluoro- methoxy)- phenyl)-methanamine C₁₄H₁₀F₄N₂O (286.22) 9   C

(S)-(6-chloro- quinolin-3-yl)- (3-(trifluoro- methyl)- pyridin-2-yl)-methanamine C₁₆H₁₁ClF₃N₃ (337.73) 10  C

(S)-(4-chloro- phenyl)(3- (trifluoro- methyl)- pyridin-2-yl)-methanamine C₁₃H₁₀ClF₃N₂ (286.68) 11  C

(S)-(8-chloro- quinolin-3-yl)- (3-(trifluoro- methyl)- pyridin-2-yl)-methanamine C₁₆H₁₁ClF₃N₃ (337.73) 12  C

(S)-(7- methoxyquino- lin-3-yl)(3- (trifluoro- methyl)- pyridin-2-yl)-methanamine C₁₇H₁₄F₃N₃O (333.31) 13  C

(S)-(5-chloro- quinolin-3-yl)- (3-(trifluoro- methyl)- pyridin-2-yl)-methanamine C₁₆H₁₁ClF₃N₃ (337.73) 14  C

(S)-quinolin- 3-yl(3- (trifluoro- methyl)- pyridin-2-yl)- methanamineC₁₆H₁₂F₃N₃ (303.28) 15  A

(S)-(3-chloro- phenyl)(3- (trifluoro- methyl)- pyridin-2-yl)-methanamine C₁₃H₁₀ClF₃N₂ (286.68) 16  B

(S)-p-tolyl(3- (trifluoro- methyl)- pyridin-2-yl)- methanamineC₁₄H₁₃F₃N₂ (266.26) 17  A

(S)- naphthalen-2- yl(3-(trifluoro- methyl)- pyridin-2-yl)- methanamineC₁₇H₁₃F₃N₂ (302.29) 18  B

(S)-(3-fluoro- phenyl)(3- (trifluoro- methyl)- pyridin-2-yl)-methanamine C₁₃H₁₀F₄N₂ (270.23) 19  A

(S)-(3- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin-2-yl)- methanamine C₁₄H₁₀F₆N₂ (320.23) 20  C

(S)-(8-fluoro- quinolin-3-yl)- (3-(trifluoro- methyl)- pyridin-2-yl)-methanamine C₁₆H₁₁F₄N₃ (321.27) 21  B

(S)-m-tolyl(3- (trifluoro- methyl)- pyridin-2-yl)- methanamineC₁₄H₁₃F₃N₂ (266.26) 22  C

(S)-quinolin- 6-yl(3- (trifluoro- methyl)- pyridin-2-yl)- methanamineC₁₆H₁₂F₃N₃ (303.28) 23  C

(S)-(5-chloro- pyridin-2-yl)- (3-(trifluoro- methyl)- pyridin-2-yl)-methanamine C₁₂H₉ClF₃N₃ (287.67) 24  C

(S)-(8- methoxyquino- lin-3-yl)(3- (trifluoro- methyl)- pyridin-2-yl)-methanamine C₁₄H₁₀F₆N₂ (333.31) 25  B

(S)-(3- methoxyphenyl)- (3-(trifluoro- methyl)- pyridin-2-yl)-methanamine C₁₄H₁₃F₃N₂O (282.26) 26  B

(S)-(3-fluoro- 4-(trifluoro- methoxy)- phenyl)(3- (trifluoro- methyl)-pyridin-2-yl)- methanamine C₁₄H₉F₇N₂O (354.22) 27  B

(S)-(4-fluoro- phenyl)(3- (trifluoro- methyl)- pyridin-2-yl)-methanamine C₁₃H₁₀F₄N₂ (270.23) 28  B

(S)-phenyl(3- (trifluoro- methyl)- pyridin-2-yl)- methanamine C₁₃H₁₁F₃N₂(252.24) 29  B

(S)-(4- ethylphenyl)- (3-(trifluoro- methyl)- pyridin-2-yl)- methanamineC₁₅H₁₅F₃N₂ (280.29) 30  A

(S)-2-(3- (trifluoro- methyl)- phenyl)-1-(3- (trifluoro- methyl)-pyridin-2-yl)- ethanamine C₁₅H₁₂F₆N₂ (334.26) 31  B

(S)-2-(3- chlorophenyl)- 1-(3- (trifluoro- methyl)- pyridin-2-yl)-ethanamine C₁₄H₁₂ClF₃N₂ (300.71) 32  B

(S)-2-(3- methoxyphenyl)- 1-(3- (trifluoro- methyl)- pyridin-2-yl)-ethanamine C₁₅H₁₅F₃N₂O (296.29) 33  B

(S)-2-(2- chlorophenyl)- 1-(3- (trifluoro- methyl)- pyridin-2-yl)-ethanamine C₁₄H₁₂ClF₃N₂ (300.71) 34  B

(S)-2-(2- methoxyphenyl)- 1-(3- (trifluoro- methyl)- pyridin-2-yl)-ethanamine C₁₅H₁₅F₃N₂O (296.29) 35  A

(S)-(3-chloro- pyridin-2-yl)- (4-(trifluoro- methyl)- phenyl)-methanamine C₁₃H₁₀ClF₃N₂ (286.68) 36  A

(S)-(3,4- dichloro- phenyl)(3- fluoropyridin- 2-yl)- methanamineC₁₂H₉Cl₂FN₂ (271.12) 37¹ A

(S)-(2- bromophenyl)- (4-(trifluoro- methyl)- phenyl)- methanamineC₁₄H₁₁BrF₃N (330.14) 38¹ A

(S)-(3-fluoro- 4-(trifluoro- methyl)- phenyl)(2- (trifluoro- methyl)-phenyl)- methanamine C₁₅H₁₀F₇N (337.24) 39¹ A

(S)-(2,6- difluoro- phenyl)(4- (trifluoro- methyl)- phenyl)- methanamineC₁₄H₁₀F₅N (287.23) 40² A

(5- bromothiazol- 4-yl)(4-(trifluoro-methyl)- phenyl)-methanamineC₁₁H₈BrF₃N₂S (337.16) 41  B

(S)-3-phenyl- 1-(3- (trifluoro-methyl)- pyridin-2-yl)-prop-2-yn-1-amineC₁₅H₁₁F₃N₂ (276.26) ¹These amines were prepared employing(R)-2-methylpropane-2-sulfinamide in the first step (Scheme 5). Forreversal of stereochemistry observed in the Ellman sulfonyliminechemistry observed with 2-pyridyl substrates, see Kuduk, S.D.; DiPardo,R. M.; Chang, R. K.; Ng, C.; Bock, M. G. Tetrahedron Lett. 2004, 45,6641-6643. ²Prepared employing racemic 2-methylpropane-2-sulfinamide inthe first step (Scheme 5)

Intermediate 42:(S)-(4-(Trifluoromethyl)phenyl)(4-(trifluoromethyl)pyridin-3-yl)methanamine

Step 1: N-Methoxy-N-methyl-4-(trifluoromethyl)nicotinamide

To a solution of 4-(trifluoromethyl)nicotinic acid (2.11 g, 11.04 mmol)and N,O-dimethylhydroxylamine hydrochloride (1.077 g, 11.04 mmol) in DCM(20 mL) was added N-ethyl-N-isopropylpropan-2-amine (3.78 mL, 22.08mmol), and HATU (4.20 g, 11.04 mmol). The reaction was stirred at rtunder N₂ for 5 h. The reaction was then diluted with H₂O (50 mL) andextracted with DCM (2×50 mL). The organic layers were combined, dried(MgSO₄), and concentrated to give the amide. Purification by ISCO (80 gSiO₂, 10-50% EtOAc/hexanes) givesN-methoxy-N-methyl-4-(trifluoromethyl)nicotinamide as a yellow oil.

Step 2:(R)-2-Methyl-N-((4-(trifluoromethyl)pyridin-3-yl)methylene)propane-2-sulfinamide

To a solution of N-methoxy-N-methyl-4-(trifluoromethyl)nicotinamide(1.50 g, 6.41 mmol) in THF (20 mL) at 0° C. was addeddiisopropylaluminum hydride (7.69 mL, 7.69 mmol) (1.0 M in hexanes).After addition, the reaction was immersed in an ice/water bath andstirred for 1 h. Additional diisopropylaluminum hydride (7.69 mL, 7.69mmol) was added, and the reaction was stirred 1 h at 0° C. The reactionwas quenched by slow addition of H₂O (2 mL) followed by addition ofsaturated aqueous sodium potassium tartrate (100 mL). The reaction wasdiluted with Et₂O and stirred at rt for 1 h. The organic layer wasseparated, and the aqueous layer was extracted with Et₂O. The combinedorganic layers were dried (MgSO₄), and the solution was concentrated to10 mL in vacuo to give a solution of the aldehyde which was used in thenext step without further purification.

To a the solution of 4-(trifluoromethyl)nicotinaldehyde from above wasadded DCM (10 mL), (R)-2-methylpropane-2-sulfinamide (1.553 g, 12.81mmol; See Table 1, footnote 1) (AK Scientific) and copper sulfate (4.09g, 25.6 mmol) (Aldrich, anhydrous). The suspension was stirred at rtunder N₂ for 68 h. The suspension was then filtered through Celite®brand filter agent, and the solid was washed with DCM (2×20 mL). Thefiltrates were concentrated and purified by ISCO (40 g, SiO₂, 10-50%EtOAc/hexane) to give(R)-2-methyl-N-((4-(trifluoromethyl)pyridin-3-yl)methylene)propane-2-sulfinamideas a light yellow oil.

Step 3:(S)-(4-(Trifluoromethyl)phenyl)(4-(trifluoromethyl)pyridin-3-yl)-methanamineHydrochloride

Following the procedure detailed above for Intermediate 2, steps 3-4gave the title compound as a white solid.

Intermediate 43:(S)-(3-Methoxypyridin-2-yl)(4-(trifluoromethyl)phenyl)-methanamine

Step 1.(S,E)-N-((3-Methoxypyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide

To a solution of 3-methoxy-pyridine-2-carbaldehyde (2.95 g, 21.51 mmol)in DCM (26 mL) was added (S)-2-methylpropane-2-sulfinamide (5.3 g, 43.7mmol) and copper(II) sulfate (6.95 g, 43.5 mmol). The suspension wasstirred at rt under argon for 18 hours, filtered, and the solid washedwith DCM (2×20 mL). The filtrates were concentrated, and the productthus obtained was purified by silica gel flash column chromatography(using a 80G ISCO cartridge) and eluted using hexanes/EtOAc gradientfollowed by DCM/MeOH to yield the desired product(S,E)-N-((3-methoxypyridin-2-yl)methylene)-2-methylpropane-2-sulfinamideas a light-yellow solid after drying under high vacuum.

Step 2.(S)—N—((S)-(3-Methoxypyridin-2-yl)(4-(trifluoromethyl)phenyl)-methyl)-2-methylpropane-2-sulfinamide

To a 150 mL round-bottomed flask containing magnesium turnings (0.370 g,15.22 mmol) and Et₂O (10 mL) was added diisobutylaluminum hydride, 1.0Msolution in THF (0.095 mL, 0.095 mmol) followed by dropwise addition of1-bromo-4-(trifluoromethyl)benzene (0.8 mL, 5.71 mmol). The solution wasstirred for 2.0 hours during which it turned from turbid to dark browncolor. The reaction mixture was cooled to −78° C. in a dry ice/actonebath, then a solution of(S,E)-N-((3-methoxypyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide(0.920 g, 3.83 mmol) in THF (10 mL) was added dropwise over 5 minutes.The reaction was stirred for 14 hours during which it warmed to rt. Thereaction was then quenched with saturated aqueous NH₄Cl (30 mL) and H₂O(25 mL) and extracted with EtOAc (2×100 mL). The combined organic layerswere dried over anhydrous sodium sulfate and concentrated to yield theinitial product which was purified by silica gel flash columnchromatography (using a 40G ISCO cartridge) and eluted usinghexanes/EtOAc gradient to yield the desired product(S)—N—((S)-(3-methoxypyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-2-methylpropane-2-sulfinamideas an yellow oil.

Step 3.(S)-(3-Methoxypyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamine

A solution of(S)—N—((S)-(3-methoxypyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-methylpropane-2-sulfinamide(0.576 g, 1.491 mmol) in MeOH (6 mL) was treated with hydrochloric acid,4.0 M solution in 1,4-dioxane (0.75 mL, 3.00 mmol) and stirred at rt for2 h. The reaction was concentrated on the rotary evaporator resulting ina gummy residue which was taken up in EtOAc (100 mL), saturated aqueousNaHCO₃ (50 mL), and H₂O (25 mL). The resulting mixture was transferredto a separatory funnel and after vigorous extraction, the organic layerwas separated, dried over anhydrous sodium sulfate, and concentrated toyield the product(S)-(3-methoxypyridin-2-yl)(4-(trifluoromethyl)-phenyl)methanamine as alight-brown oil which was used without further purification in the nextstep.

Intermediate 44:(S)-(3-Methylpyridin-2-yl)(4-(trifluoromethyl)phenyl)-methanamineHydrochloride

Step 1.(S,E)-2-Methyl-N-((3-methylpyridin-2-yl)methylene)propane-2-sulfinamide

To a solution of 3-methyl-2-pyridinecarboxaldehyde (3.243 g, 26.8 mmol)in DCM (18 mL) was added (S)-2-methylpropane-2-sulfinamide (6.55 g, 54.0mmol) and copper(II) sulfate (8.72 g, 54.6 mmol). The suspension wasstirred at rt for 17 hours, filtered, and the solid was washed with DCM(2×35 mL). The filtrates were concentrated, and the resulting productwas purified by silica gel flash column chromatography (using a 80G ISCOcartridge) and eluted using DCM/MeOH gradient to yield the desiredproduct(S,E)-2-methyl-N-((3-methylpyridin-2-yl)methylene)propane-2-sulfinamideas a yellow solid.

Step 2.(S)-2-Methyl-N—((S)-(3-methylpyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)propane-2-sulfinamide

A 250 mL round-bottomed flask containing magnesium turnings (0.685 g,28.2 mmol) and Et₂O (25 mL) was added diisobutylaluminum hydride 1.0 Msolution in hexanes (0.18 mL, 0.180 mmol) followed by dropwise additionof 4-bromobenzotrifluoride (2.0 mL, 14.28 mmol). The solution wasstirred for 1.5 hours during which it turned from turbid to dark brownin color. The reaction mixture was cooled to −78° C. in a dry ice/actonebath and then a solution of(S,E)-2-methyl-N-((3-methylpyridin-2-yl)methylene)propane-2-sulfinamide(2.15 g, 7.67 mmol) in THF (15 mL) was added dropwise over 5 minutes.The reaction was stirred for 5 hours during which it warmed to rt. Thereaction was quenched with saturated aqueous NH₄Cl (50 mL) and H₂O (25mL). The reaction mixture was extracted with EtOAc (2×100 mL). Thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated to yield the initial product which was purified by silicagel flash column chromatography (using a 80G ISCO cartridge) and elutedusing hexanes/EtOAc gradient to yield the desired product(S)-2-methyl-N-((S)-(3-methylpyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-propane-2-sulfinamideas an yellow solid.

Step 3. (S)-(3-Methylpyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamineHydrochloride

A solution of(S)-2-methyl-N—((S)-(3-methylpyridin-2-yl)(4-(trifluoro-methyl)phenyl)methyl)propane-2-sulfinamide(0.355 g, 0.958 mmol) in MeOH (10 mL) was treated with hydrogenchloride, 4.0 M solution in 1,4-dioxane (0.6 mL, 2.400 mmol) and stirredat rt. The reaction was concentrated on the rotary evaporator resultingin a gummy residue. The residue(S)-(3-methylpyridin-2-yl)-(4-(trifluoromethyl)phenyl)methanaminehydrochloride was used in the next steps without further purification.

Intermediate 45:(S)-(3-Fluoro-4-(trifluoromethyl)phenyl)(3-(trifluoro-methyl)pyridin-2-yl)methanamineHydrochloride

Step 1.(S,E)-N-(3-Fluoro-4-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide

To a solution of 3-fluoro-4-(trifluoromethyl)benzaldehyde (5.7 g, 29.7mmol) in DCM (60 mL) was added (S)-2-methylpropane-2-sulfinamide (7.19g, 59.3 mmol) and copper (II) sulfate (18.94 g, 119 mmol). Thesuspension was stirred at rt under N₂ for 20 h. The suspension was thenfiltered through Celite® brand filter agent, and the solids were washedwith DCM (2×20 mL). The filtrates were concentrated and purified by ISCO(120 g, SiO₂, 10-50% EtOAc/hexanes) to give(S,E)-N-(3-fluoro-4-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamideas a white solid.

Step 2.(S)—N—((S)-(3-Fluoro-4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)-pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide

To a solution of 2-(tributylstannyl)pyrimidine (425 mg, 1.151 mmol) inTHF (3 mL) at −78° C. was added n-butyllithium (0.720 mL, 1.151 mmol)(1.6 M in hexanes). The reaction was stirred at −78° C. for 1.5 h andthen(S,E)-N-(3-fluoro-4-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide(408 mg, 1.382 mmol) in THF (1 mL) was added. The cooling bath was thenremoved as the reaction was allowed to warm to rt and stirred for 1 h.LCMS showed 2 products with a ratio of 10:1. The reaction was quenchedwith saturated aqueous NH₄Cl (5 mL) and H₂O (5 mL). The reaction mixturewas extracted with EtOAc (2×5 mL). The organic layers were combined,dried (MgSO₄), and concentrated to give the product. Purification byISCO (12 g SiO₂, 20-80% EtOAc/hexanes) gave the major product,(S)—N—((S)-(3-fluoro-4-(trifluoromethyl)phenyl)-(pyrimidin-2-yl)methyl)-2-methylpropane-2-sulfinamide.

Step 3.(S)-(3-Fluoro-4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methanamineHydrochloride

To a solution of(S)—N—((S)-(3-fluoro-4-(trifluoromethyl)phenyl)-(pyrimidin-2-yl)methyl)-2-methylpropane-2-sulfinamide(100 mg, 0.266 mmol) in MeOH (5 mL) was added hydrogen chloride (0.200mL, 0.799 mmol) (4.0 M in 1,4-dioxane). The reaction was stirred for 2 hat rt under N₂ and then concentrated in vacuo to give the amine as thehydrochloride salt which was used in the next step without furtherpurification.

Intermediate 46:(S)-(3-(Prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methanamineHydrochloride

Step-1. 3-Bromo-2-dibromethyl-pyridine

To a solution of 3-bromo-picoline (25 g, 0.145 mol) in CCl₄ was addedN-bromosuccinimide (51.66 g, 0.29 mol) and benzoylperoxide (2.5 g, 0.018mol). The mixture was then gradually heated to reflux and stirred for 30h. The reaction mixture was then cooled to rt, the succinimide wasremoved by filtration, and the filtrate was concentrated under reducedpressure. The resulting product was purified by flash columnchromatography using silica (100-200 mesh) with EtOAc:hexane (0.1:09) aseluent to furnish pure 3-Bromo-2-dibromomethyl-pyridine. ¹H-NMR (400MHz, CDCl₃): δ7.66-7.68 (d, 1H), 7.84-7.88 (d, 1H), 7.13-7.17 (t, 2H).

Step-2. 3-Bromo-pyridine-2-carbaldehyde

A suspension of 3-bromo-2-dibromomethyl-pyridine (10.0 g, 30.32 mmole)in morpholine (30.0 mL) was heated to 60° C. for 1 h. The reactionmixture was cooled to rt and diluted with EtOAc (200 mL). The pH wasadjusted to 4.0 by adding citric acid (40.0 g). The reaction mixture wasthen extracted with EtOAc (3×200 mL) and the combined organic layerswere dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography using silica (100-200mesh) using 3% EtOAc in hexane as eluent to give3-bromo-pyridine-2-carbaldehyde. ¹H-NMR (400 MHz, CDCl₃): δ 10.23 (s,1H), 8.74-8.76 (d, 1H), 8.02-8.04 (d, 1H), 7.26-7.38 (t, 1H).

Step 3.(S,E)-N-((3-Bromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide

A mixture of 3-bromo piconaldehyde (10 g, 53.8 mmol), copper sulfate(3.98 mL, 81 mmol) and (S)-2-methylpropane-2-sulfinamide (6.84 g, 56.4mmol) in DCM (100 mL) was stirred at rt overnight. The solid wasfiltered off and the filtrate concentrated under vacuum. The residue waspurified by column chromatography using silica (100-200 mesh) with 20%EtOAc in n-hexane as eluent to give(S,E)-N-((3-bromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamideas yellow oil. ¹H-NMR (400 MHz, CDCl₃): δ9.0 (s, 1H), 8.74-8.76 (d, 1H),7.9-8.04 (d, 1H), 7.26-7.38 (t, 1H), 5.2 (d, 1H), 1.3 (s, 9H).

Step 4. (S)-2-Methyl-propane-2-sulfinic Acid((3-bromo-pyridin-2-yl)-(4-trifluoromethyl-phenyl)-methyl)-amide

To a stirred suspension of magnesium (2.143 g, 88 mmol) in THF (50 mL),was added 4-bromobenzotrifluoride (5.06 mL, 36.2 mmol). Stirring wascontinued for 4 h (caution: slightly exothermic, cooled with a waterbath if needed). The resulting mixture was added to a stirred solutionof(S,E)-N-((3-bromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide(5.1 g, 17.64 mmol) in THF (100 mL) at −78° C. in a dropwise fashion.The mixture was stirred for another hour after addition and the reactionwas then quenched with saturated aqueous NH₄Cl, extracted with Et₂O(3×20 mL), dried over Na₂SO₄, concentrated, and purified by columnchromatography using silica (100-200 mesh) with 5% EtOAc in hexane aseluent to give the title compound as a brown oil.

Step 5.(S)-tert-Butyl((3-bromopyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamate

To a cooled (0° C.) stirred solution of (S)-2-methyl-propane-2-sulfinicacid ((3-bromo-pyridin-2-yl)-(4-trifluoromethyl-phenyl)-methyl)-amide(5.0 g, 11.49 mmol) in DCM/EtOH (1/1.60 mL) was added 4.0 M HCl in1,4-dioxane (14.36 mL, 57.4 mmol). Stirring was continued for 2 h andthen DIPEA (10.00 mL, 57.4 mmol) was added, followed by di-tert-butyldicarbonate (4.00 mL, 17.23 mmol) added. The resulting mixture wasstirred at rt overnight, diluted with H₂O, and extracted with DCM (3×100mL). The combined organic layers were dried over Na₂SO₄ and concentratedunder reduced pressure. The residue thus obtained was purified by silicagel (100-200 mesh) column chromatography using 5% EtOAc in hexane aseluent to give the title compound as a white solid. ¹H-NMR (400 MHz,DMSO-d₆): δ8.5 (dd, 1H), 7.81 (dd, 1H), 7.52 (s, 4H), 7.2 (dd, 1H) 6.51(d, 1H), 6.32 (d. 1H), 1.41 (s, 9H).

Step 6. (S)-(3-Bromopyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamineHydrochloride

To a solution of (S)-tert-butyl((3-bromopyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)carbamate (2.0g, 4.64 mmol) in MeOH (10 mL) was added hydrogen chloride (3.48 mL,13.91 mmol) (4.0 M in 1,4-dioxane). The reaction was stirred for 27 h atrt under N₂. The reaction was concentrated in vacuo to give the aminewhich was used without further purification in subsequent steps. MS (ESIpos. ion) m/z: 331.0, 332.9 (M+H).

Intermediate 47:(S)-(3-(Prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methanamineHydrochloride

Step 1. (S)-tert-Butyl((3-(prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)carbamate

To a microwave vial containing (S)-tert-butyl((3-bromopyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamate (500mg, 1.159 mmol) and a stir bar was added 1,4-dioxane (6 mL). To thissolution was added tetrakis(triphenyl-phosphine)palladium(0) (67.0 mg,0.058 mmol, 0.05 eq) and tributyl(prop-1-yn-1-yl)stannane (458 mg, 1.391mmol, 1.2 eq). The vial was capped and irradiated in a microwave at 120°C. for 20 min. The vial was allowed to cool, diluted with hexanes (5 mL)and loaded directly to a normal phase silica gel column (80 g ISCO, 0 to40% EtOAc in hexanes) to provide (S)-tert-butyl((3-(prop-1-yn-1-yl)-pyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamateas a white solid.

Step 2.(S)-(3-(Prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoromethyl)phenyl)-methanamineHydrochloride

To a 500 mL round bottom flask containing (S)-tert-butyl((3-(prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamate(400 mg, 1.025 mmol) was added DCM (8 mL) and the mixture was stirred at23° C. for 2 min. At this time, hydrogen chloride (4N in 1,4-dioxane)(37.4 mg, 1.025 mmol) (4 mL) was added via syringe. The reaction wasstirred for 3 h then the volatiles were removed via rotoryevaporator.The solid was placed on high vacuum overnight to give(S)-(3-(prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoromethyl)phenyl)-methanaminehydrochloride as a white solid.

Intermediate 48:(S)-(3-((3-Methyloxetan-3-yl)ethynyl)pyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamineHydrochloride

To a microwave flask containingtrimethyl((3-methyloxetan-3-yl)-ethynyl)silane (0.585 g, 3.48 mmol) wasadded THF (7.73 mL) and the mixture was stirred at 23° C. for 2 min. Atthis time, (S)-tert-butyl((3-bromopyridin-2-yl)-(4-trifluoromethyl)phenyl)methyl)carbamate (1.00g, 2.319 mmol), tetrabutylammonium fluoride (0.909 g, 3.48 mmol),copper(I) iodide (0.022 g, 0.116 mmol) and lastlytetrakis(triphenylphosphine)palladium(0) (0.134 g, 0.116 mmol) wereadded to the flask. The flask was heated to 85° C. for 90 min. The flaskwas allowed to cool and then subjected to a EtOAc (100 mL) and NaHCO₃(sat, 1M, 100 mL) work up. The aq layer was extracted with EtOAc (3×).The combined organics were washed with brine, dried with sodium sulfate,filtered and concentrated to give an oil (1.72 g). The oil thus obtainedwas subjected to silica gel chromatography (120 g ISCO, 20 to 35% EtOAcin hexanes) to give (S)-tert-butyl((3-((3-methyloxetan-3-yl)ethynyl)pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)carbamateas a pale yellow oil.

(S)-tert-Butyl((3-((3-methyloxetan-3-yl)ethynyl)pyridin-2-yl)(4-(trifluoro-methyl)phenyl)methyl)carbamatefrom above was prepared by following the procedure described for thepreparation of Intermediate 47, Step 2 to give the title compound as awhite solid.

Intermediate 49:(1S)-(3-(2,2-Dimethylcyclopropyl)pyridin-2-yl)(4-(trifluoro-methyl)phenyl)methanamineHydrochloride

A mixture of (S)-tert-butyl(3-bromopyridin-2-yl)(4-(trifluoromethyl)-phenyl)methylcarbamate (1.50g, 3.48 mmol), potassium (2,2-dimethylcycloprop-yl)trifluoroborate(0.857 g, 4.87 mmol), potassium phosphate (2.58 g, 12.17 mmol),dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.314 g, 0.765mmol), and palladium acetate (0.094 g, 0.417 mmol) in toluene/H₂O (10:1,11 mL) was heated at 100° C. for 24 h. The reaction mixture was cooled,diluted with H₂O, and extracted with EtOAc (3×). The combined extractswere dried over MgSO₄, concentrated and purified by ISCO (10%EtOAc/hexanes) to give a colorless oil which was dissolved in DCM (3 mL)and was treated with 4 mL of 4M HCl in 1,4-dioxane. The solution wasstirred at rt overnight and concentrated to dryness to give the titlecompound as an off white solid. MS (ESI pos. ion) m/z: 321.0 (M+H).

Intermediate 50:(S)-(3-Allylpyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamineHydrochloride

A mixture of (S)-tert-butyl(3-bromopyridin-2-yl)(4-(trifluoromethyl)-phenyl)methylcarbamate (1.00g, 2.319 mmol), allylboronic acid pinacol ester (0.507 mL, 3.01 mmol),cesium fluoride (0.171 mL, 4.64 mmol), and (Ph₃P)₄Pd (0.536 g, 0.464mmol) in 1,4-dioxane (10 mL) was heated by microwave at 125° C. for 30min. The mixture was cooled, taken up in H₂O, extracted with Et₂O (3×25mL), the combined organic layers were dried over MgSO₄, concentrated andpurified by ISCO (0-50% EtOAc/hexanes). The residue was dissolved in DCM(10 mL) was added HCl in 4M p-dioxane (4.64 mL, 18.55 mmol). Stirringwas continued for 2 h, and the solution concentrated to the dryness togive the title compound as a white solid. MS (ESI pos. ion) m/z: 293.0(M+H).

Intermediate 51:(S)-(3-Neopentylpyridin-2-yl)(4-(trifluoromethyl)phenyl)-methanamineHydrochloride

A mixture of (S)-tert-butyl(3-bromopyridin-2-yl)(4-(trifluoromethyl)-phenyl)methylcarbamate (0.500g, 1.159 mmol), bis(tri-t-butylphosphine)-palladium (0) (0.119 g, 0.232mmol), and neopentylzinc(II) bromide (4.75 mL, 2.377 mmol) in THF (5 mL)was stirred at 135° C. by microwave for 30 min. The reaction mixture wascooled, quenched with saturated aqueous NH₄Cl, and extracted with EtOAc(3×25 mL). The combined organic extracts were dried over MgSO₄,concentrated, and purified by ISCO (0-40% EtOAc/hexanes) to give thecarbamate intermediate. The carbamate was dissolved in DCM (5 mL) and 4MHCl in 1,4-dioxane (2 mL) was added. The reaction mixture was stirred atrt overnight, and concentrated to dryness to give the title compound asa white solid. MS (ESI pos. ion) m/z: 323.0 (M+H).

Intermediate 52:(S)-(3-Neopentylpyridin-2-yl)(4-(trifluoromethyl)phenyl)-methanamineHydrochloride

Step 1. (E)-N-(3,4-Dichlorobenzylidene)-2-methylpropane-2-sulfinamide

A 1-L round-bottomed flask was charged with 3,4-dichlorobenzaldehyde(25.0 g, 143 mmol), 2-methylpropane-2-sulfinamide (17.3 g, 143 mmol),and 200 mL of THF. To this was added Ti(OEt)₄ (65.2 g, 286 mmol) over 5min. The reaction was stirred at rt for 5 h and then poured onto brine.The resulting white precipitate was removed by filtration, and thefilter cake was washed with EtOAc. The filtrate was transferred to aseparatory funnel and the layers were separated. The organic layers werecombined and dried (MgSO₄), filtered, and concentrated to give(E)-N-(3,4-dichlorobenzylidene)-2-methylpropane-2-sulfinamide as a whitesolid.

Step 2.(S)-(3-Neopentylpyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamineHydrochloride

A 250-mL round-bottomed flask was charged with 2-iodopyridine (1.0 g,4.88 mmol) and 50 mL of THF. The resulting mixture was cooled to −100°C. and then n-BuLi (2.5 M in hexanes, 5.3 mL, 13 mmol) was added at sucha rate that the internal temp did not rise above −97° C. After 15 min at−100° C., (E)-N-(3,4-dichlorobenzylidene)-2-methylpropane-2-sulfinamide(1.36 g, 4.88 mmol) was added and stirring was continued for 1 h at−100° C. 30 mL of 1M HCl in ether was added, and the mixture was allowedto warm to rt. Once at rt, 5 mL of MeOH was added and the mixture wasstirred for an additional 1 h. The resulting precipitate was collectedby filtration to give (3,4-dichlorophenyl)(pyridin-2-yl)-methanaminehydrochloride as a white solid.

Intermediate 53:1-(4-((S)-Amino(3-(trifluoromethyl)pyridin-2-yl)methyl)-phenyl)ethanolHydrochloride

Step 1.(S)—N—((S)-(4-Formylphenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide

Magnesium metal (0.200 g, 8.23 mmol) was activated using a crystal ofiodine followed by the addition of THF (4 mL).1-Bromo-4-(diethoxymethyl)-benzene (2.0 g, 7.72 mmol) was added and themixture allowed to sit without stirring for 5 minutes. Gas evolution wasobserved and the colour of the iodine mostly disappeared. Stirring wasthen initiated and additional dry THF (20 mL) was added. After stirringfor 2 hours, the mixture was allowed to settle. The supernatant wasadded to a solution of(S,E)-2-methyl-N-((3-(trifluoromethyl)-pyridin-2-yl)methylene)propane-2-sulfinamide(0.450 g, 1.617 mmol) in dry THF (10 mL). The resulting reaction mixturewas stirred overnight. Saturated aqueous NH₄Cl (10 mL) was addedfollowed by H₂O (80 mL) and EtOAc (100 mL). The phases were mixed andseparated. The organic layer was dried with MgSO₄ and evaporated todryness under reduced pressure. The acetal was further dried under highvacuum. The acetal was dissolved in EtOAc (50 mL) and treated with 50%TFA in H₂O (50 mL). The solution was stirred vigorously for 20 minutes.Water (200 mL), EtOAc (100 mL), and Et₂O (100 mL) were then added andthe phases separated. The aqueous layer was removed, and the organiclayer was washed with additional H₂O (2×200 mL). The organic layer wasthen washed with saturated aqueous NaHCO₃ (3×100 mL, strong gasevolution) followed by H₂O (100 mL) and finally brine (100 mL). Theorganic layer was dried with MgSO₄ and evaporated to dryness underreduced pressure. Purification using silica chromatography (hexane toEtOAc gradient) gave the desired(S)—N—((S)-(4-formylphenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamideas an oil.

Step 2.1-(4-((S)-Amino(3-(trifluoromethyl)pyridin-2-yl)methyl)phenyl)-ethanolHydrochloride

(S)—N—((S)-(4-Formylphenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(0.200 g, 0.520 mmol) was dissolved in dry THF (30 mL) and cooled in anice bath. Methylmagnesium bromide (3M in Et₂O, 0.50 mL, 1.50 mmol) wasadded dropwise and the reaction stirred. The resulting mixture wasstirred for 1 h and then quenched by addition of saturated aqueous NH₄Cl(10 mL). H₂O (100 mL) and EtOAc (100 mL) were added, and the phases weremixed and separated. The organic layer was dried with MgSO₄ andevaporated to dryness under reduced pressure. Purification using silicachromatography (hexane to EtOAc gradient) gave impure material which wasfurther purified using reverse phase HPLC to give the desired(S)—N-((1S)-(4-(1-hydroxyethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide.

The sulfinamide was then subjected to the hydrolysis conditions similarto those described above in Scheme 6, Step 4 to give the title compound.

Intermediate 54: (S)-Pyridin-2-yl(4-(trifluoromethyl)phenyl)methanaminebis(2,2,2-trifluoroacetate)

Step 1. (S)-tert-Butyl(pyridin-2-yl(4-(trifluoromethyl)phenyl)methyl)-carbamate

To a solution of (S)-tert-butyl((3-bromopyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)carbamate (2.24g, 5.19 mmol) in MeOH (20 mL) was added palladium hydroxide, (20 wt % Pd(dry basis) on carbon, wet, degussa type) (0.365 g, 2.60 mmol). Theresulting mixture was then stirred at rt under H₂ overnight. The mixturewas filtered through Celite® brand filter agent and the solids werewashed with a solution of MeOH/EtOAc (1:1, 3×20 mL). The combinedfiltrates were concentrated and dried to give the desired product as ayellow oil, which was used in the next step without furtherpurification.

Step 2. (S)-Pyridin-2-yl(4-(trifluoromethyl)phenyl)methanaminebis(2,2,2-trifluoroacetate)

To a solution of (S)-tert-butyl(pyridin-2-yl(4-(trifluoromethyl)phenyl)methyl)carbamate (1.83 g, 5.19mmol) in DCM (12 mL) was added TFA (3.86 mL, 51.9 mmol). The resultingmixture was then stirred at rt for 1 h. The mixture was thenconcentrated and dried to give the title compound as a yellow oil whichwas used without further purification in the amide coupling step.

Intermediates 55-57: 4-Hydroxyquinoline-6-carboxylic Acid (55),4-chloro-quinoline-6-carboxylic Acid (56), and2-oxo-1,2,4a,8a-tetrahydroquinoline-6-carboxylic Acid (57)

Step 1. Methyl quinoline-6-carboxylate

To a solution of quinoline-6-carboxylic acid (1.00 g, 5.77 mmol) in MeOH(10 mL) was added hydrogen chloride (2.00 mL, 8.00 mmol) (4.0M in1,4-dioxane). The reaction was stirred 18 h at rt, LCMS shows <10%conversion. Additional hydrogen chloride (2.00 mL, 8.00 mmol) was addedand the reaction heated to 50° C. in an oil bath 36 h. The reaction wascooled to rt and concentrated in vacuo. The solid was dissolved in DCMand extracted with sat. aqueous NaHCO₃ (2×50 mL). The organic layer wasdried (MgSO₄), and concentrated to give the product which was usedwithout further purification in the next step.

Step 2. 6-(Methoxycarbonyl)quinoline-N-oxide

To a solution of methyl quinoline-6-carboxylate from above in DCM (10mL) was added 3-chlorobenzoperoxoic acid (1.991 g, 11.54 mmol). Thereaction was stirred 21 h at rt. The mixture was then diluted withsaturated aqueous NaHCO₃ (40 mL), and the mixture was extracted with DCM(2×30 mL). The organic layers were combined, washed with saturatedaqueous NaCl (40 mL), dried (MgSO₄), and concentrated. The N-oxide wasisolated as an orange solid which was used without purification in thenext step.

Step 3. Methyl 4-chloroquinoline-6-carboxylate and Methyl2-chloro-quinoline-6-carboxylate

To 6-(methoxycarbonyl)quinoline-N-oxide from the above step was addedphosphoryl trichloride (5 mL, 54.6 mmol). The resulting mixture was thenstirred at rt under N₂ for 2 h. The reaction was then slowly quenched byaddition to an ice cold solution of saturated aqueous NaHCO₃ (50 mL) inan ice bath with rapid stirring. The aqueous solution was extracted withEtOAc (3×50 mL). The organic layers were combined, washed with saturatedaqueous NaHCO₃ (25 mL), H₂O (25 mL), dried (MgSO₄), and concentrated.Purification by ISCO (40 g SiO₂, 0-50% EtOAc/hexanes) gave as the majorproduct, methyl 4-chloroquinoline-6-carboxylate (330 mg, 1.489 mmol,25.8% yield over 3 steps) (m/z=221.9) as a white solid. Also isolatedwas the more polar, methyl 2-chloroquinoline-6-carboxylate with samemass (m/z=221.9).

Step 4a. 4-Hydroxyquinoline-6-carboxylic Acid (55) and4-chloroquinoline-6-carboxylic Acid (56)

A solution of methyl 4-chloroquinoline-6-carboxylate (110 mg, 0.496mmol) in THF/5 N aqueous HCl (1:1, 2 mL) was heated to 60° C. in aheating block for 24 h. LCMS showed major product with a 56-70% peakarea corresponding to 4-hydroxyquinoline-6-carboxylic acid withhydrolysis of methyl ester (M+H=189.9). Also present was a 18-34% peakarea corresponding to 4-chloroquinoline-6-carboxylic acid. The reactionwas concentrated and used in the subsequent amide coupling steps withoutfurther purification.

Step 4b. 2-Oxo-1,2,4a,8a-tetrahydroquinoline-6-carboxylic Acid (57)

A solution of methyl 2-chloroquinoline-6-carboxylate (60 mg, 0.271 mmol)in THF/5 N aqueous HCl (1:1, 2 mL) was heated to 60° C. in a heatingblock. LCMS shows major product 86% peak area corresponding to titlecompound with hydrolysis of methyl ester (m/z=189.9). The reaction wasconcentrated and used in the subsequent amide coupling steps withoutfurther purification.

Intermediates 58-60: 4-Hydroxyquinoline-6-carboxylic Acid,4-chloro-quinoline-6-carboxylic Acid (58),2-oxo-1,2,4a,8a-tetrahydroquinoline-6-carboxylic Acid (59), and2-oxo-1,2-dihydroquinoline-7-carboxylic Acid (60)

Step 1. Methyl quinoline-7-carboxylate

To a solution of quinoline-7-carboxylic acid (1.00 g, 5.77 mmol) in MeOH(10 mL) was added hydrogen chloride (2.00 mL, 8.00 mmol) (4.0M in1,4-dioxane). The reaction was stirred for 18 h at rt (LCMS showed <10%conversion to the desired product). Additional hydrogen chloride (2.00mL, 8.00 mmol) was added, and the reaction mixture was heated to 50° C.in an oil bath for 36 h. The reaction was cooled to rt, and concentratedin vacuo. The solid was dissolved in DCM, and washed with saturatedaqueous NaHCO₃ (2×50 mL). The organic layer was dried (MgSO₄) andconcentrated to give the product, which was used without furtherpurification in the next step.

Step 2. 7-(Methoxycarbonyl)quinoline-N-oxide

To a solution of the methyl quinoline-7-carboxylate from above in DCM(10 mL) was added 3-chlorobenzoperoxoic acid (1.991 g, 11.54 mmol). Thereaction was stirred for 21 h at rt. The mixture was then diluted withsaturated aqueous NaHCO₃ (40 mL) and the mixture was extracted with DCM(2×30 mL). The organic layers were combined, washed with saturatedaqueous NaCl (40 mL), dried (MgSO₄), and concentrated. The N-oxide wasisolated as an orange solid which was used without purification in thenext step.

Step 3. Methyl 4-chloroquinoline-7-carboxylate and Methyl2-chloro-quinoline-7-carboxylate

To the N-oxide from above was added phosphoryl trichloride (10 mL, 109mmol). The resulting reaction mixture was stirred at rt under N₂ or 2 h.The reaction was then quenched by slowly adding it to an ice coldsolution of saturated aqueous NaHCO₃ (100 mL) in an ice bath with rapidstirring. The aqueous solution was extracted with EtOAc (3×50 mL), theorganic layers combined, washed with saturated aqueous NaHCO₃ (25 mL),H₂O (25 mL), dried (MgSO₄), and concentrated. Purification by ISCO (40 gSiO₂, 0-50% EtOAc/hexanes) gave methyl 4-chloroquinoline-7-carboxylateas a white solid and methyl 2-chloro-quinoline-7-carboxylate as a whitesolid.

Step 4a. 4-Hydroxyquinoline-7-carboxylic Acid (58) and4-chloroquinoline-7-carboxylic Acid (59)

A solution of methyl 4-chloroquinoline-7-carboxylate (110 mg, 0.496mmol) in THF/5 N aqueous HCl (1:1, 2 mL) was heated to 60° C. in aheating block or 22 h. LCMS showed formation of product (40% peak area)with the mass of 4-hydroxyquinoline-7-carboxylic acid (m/z (M+H)=189.9).Additional product 20% peak area corresponding to the mass of4-chloroquinoline-7-carboxylic acid (m/z (M+H)=207.9). The reaction wasconcentrated and used in the subsequent amide coupling steps withoutfurther purification.

Step 4b. 2-Oxo-1,2-dihydroquinoline-7-carboxylic Acid (60)

A solution of methyl 2-chloroquinoline-7-carboxylate (150 mg, 0.677mmol) in THF/5 N aqueous HCl (1:1, 2 mL) was heated to 60° C. in aheating block or 24 h. LCMS showed major product (47% peak area)corresponding to 2-oxo-1,2-dihydroquinoline-7-carboxylic acid (m/z(M+H)=189.9). The reaction was concentrated and used in the subsequentamide coupling steps without further purification.

Examples General Amide Formation Procedure for Examples (1-261, 287-424)

To a solution of(S)-(4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methanamine(50 mg, 0.156 mmol), the corresponding carboxylic acid (0.156 mmol), andDIPEA (0.080 mL, 0.468 mmol) in DCM or DMF (1 mL) at rt is added anamide coupling reagent such as (HATU, TBTU, or EDCI) (0.156 mmol, 1.0equiv.). The reaction was stirred 3 h at rt. The reaction was dilutedwith DMF (1 mL), filtered through a syringe filter, then purified bypreparative reverse phase HPLC (gradient elution 10-100% MeCN/0.1% TFAin H₂O). The product containing fractions were then combined and thesolvent removed by lyophilzation to provide the target compound as theTFA salt; or the product was dissolved in MeOH (1 mL) and washed throughPL-HCO₃ MP-resin, the resin was further washed with MeOH (2×0.4 mL). Thecombined filtrates were then concentrated and dried in vacuo to give thetitle compounds as free bases; or the product containing fractions wereconcentrated, the solids dissolved in DCM and the organic layerextracted with saturated aqueous NaHCO₃, the organic layer was dried,and concentrated to provide the title compounds as free bases.

TABLE 2 Examples 1-261 prepared via amide formation analogous to Scheme4 Product Product MS Ex # Amine Acid Structure Structure Name M + H 1 8

(S)-N- ((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methoxy)- phenyl)-methyl)- 6-oxo-1,6- dihydro- pyridine- 3-carbox- amide 408.0 2 8

(S)-N-((3- fluoro- pyridin-2- yl)(4- (trifluoro- methoxy)- phenyl)-methyl)- quinoline-7- carboxamide 442.0 3 4

(S)-N-((3,4- dichloro- phenyl)- (3-(trifluoro- methyl)- pyridin-2-yl)methyl)-6- hydro- xynicotin- amide 442.0 4 9

(S)-N-((6- chloro- quinolin-3- yl)(3- (trifluoro- methyl)-pyridin-2-yl)- methyl)- quinoline-7- carboxamide 493.0 5 5

(S)-N-((4- (trifluoro- methoxy)- phenyl)(3- (trifluoro- methyl)-pyridin-2-yl)- methyl)- quinoline-7- carboxamide 492.0 6 10

(S)-N-((4- chloro- phenyl)(3- (trifluoro- methyl)- pyridin-2-yl)-methyl)- quinoline-7- carboxamide 442.0 7 11

(S)-N-((8- chloro- quinolin-3- yl)(3- (trifluoro- methyl)-pyridin-2-yl)- methyl)- quinoline-7- carboxamide 493.0 8 12

(S)-N-((7- methoxy- quinolin- 3-yl)(3- (trifluoro- methyl)- pyridin-2-yl)methyl)- quinoline-7- carboxamide 489.0 9 13

(S)-N-((5- chloro- quinolin-3- yl)(3- (trifluoro- methyl)-pyridin-2-yl)- methyl)- quinoline-7- carboxamide 493.0 10 4

(S)-N-((3,4- dichloro- phenyl)- (3-(trifluoro- methyl)- pyridin-2-quinoline-7- carboxamide 475.9 11 9

(S)-N-((6- chloro- isoquinolin-3- yl)(3- (trifluoro- methyl)-pyridin-2-yl)- methyl)- isoquinoline-6- carboxamide 493.0 12 14

(S)-N- (quinolin- 3-yl(3- (trifluoro- methyl)- pyridin-2- yl)methyl)-quinoline-7- carboxamide 459.0 13 15

(S)-N-((3- chloro- phenyl)(3- (trifluoro- methyl)- pyridin-2-yl)-methyl)- quinoline-7- carboxamide 442.0 14 16

(S)-N-(p- tolyl(3- (trifluoro- methyl)- pyridin- 2-yl)- methyl)-quinoline-7- carboxamide 422.0 15 17

(S)-N- (naphthalen- 2- yl(3- (trifluoro- methyl)- pyridin-2- yl)methyl)-quinoline-7- carboxamide 458.0 16 9

(S)-N-((6- chloro- quinolin-3- yl)(3- (trifluoro- methyl)-pyridin-2-yl)- methyl)-6- hydro- xynicotin- amide 458.9 17 18

(S)-N-((3- fluoro- phenyl)(3- (trifluoro- methyl)- pyridin-2-yl)-methyl)- quinoline-7- carboxamide 426.0 18 19

(S)-N-((3- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin-2-yl)- methyl)- quinoline-7- carboxamide 476.0 19 3

(S)-N-((4- methoxy- phenyl)- (3-(trifluoro- methyl)- pyridin-2-yl)methyl)- quinoline-7- carboxamide 438.0 20 20

(S)-N-((8- fluoro- quinolin-3- yl)(3- (trifluoro- methyl)-pyridin-2-yl)- methyl)- quinoline-7- carboxamide 477.0 21 21

(S)-N-(m- tolyl(3- (trifluoro- methyl)- pyridin-2-yl)- methyl)-quinoline-7- carboxamide 422.0 22 22

(S)-N- (quinolin- 6-yl(3- (trifluoro- methyl)- pyridin-2- yl)methyl)-quinoline-7- carboxamide 458.9 23 24

(S)-N-((8- methoxy- quinolin- 3-yl)(3- (trifluoro- methyl)- pyridin-2-yl)methyl)- quinoline-7- carboxamide 489.0 24 25

(S)-N-((3- methoxy- phenyl)- (3-(trifluoro- methyl)- pyridin-2-yl)methyl)- quinoline-7- carboxamide 438.0 25 26

(S)-N-((3- fluoro- 4-methoxy- phenyl)- (3-(trifluoro- methyl)-pyridin-2- yl)methyl)- quinoline-7- carboxamide 456.0 26 53

N-((1S)- (4-(1- hydroxy- ethyl)- phenyl)(3- (trifluoro- methyl)-pyridin-2-yl)- methyl)- quinoline-7- carboxamide 452.0 27 27

(S)-N-((4- fluoro- phenyl)(3- (trifluoro- methyl)- pyridin-2-yl)-methyl)- quinoline-7- carboxamide 426.0 28 43

(S)-N-((3- methoxy- pyridin- 2-yl)(4- (trifluoro- methyl)- phenyl)-methyl)- quinoline-7- carboxamide 438.2 29 1

(S)-2- methoxy- N-((4- (trifluoro- methyl)- phenyl)- (3-(trifluoro-yl)methyl)- nicotinamide 456.0 30 1

(S)-6- methoxy- N-((4- (trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- nicotinamide 456.0 31 1

(S)-N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin-2- yl)- methyl)- pyridazine-3- carboxamide 427.1 32 1

(S)-4- methoxy- N-((4- (trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- picolinamide 456.0 33 1

(S)-6- methoxy- N-((4- (trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- picolinamide 456.0 34 1

(S)-2- methoxy- N-((4- (trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- isonicotin- amide 456.0 35 2a

N-((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)- phenyl)- methyl)-6- methoxy- nicotinamide 406.1 36 2a

N-((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)- phenyl)- methyl)-2- methoxy- nicotinamide 406.1 37 1

(S)-6- methoxy- N-((4- (trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- pyridazine-3- carboxamide 457.1 38 1

(S)-5- methoxy- N-((4- (trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- nicotinamide 456.0 39 1

(S)-2- methyl-N- ((4- (trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- isonicotin- amide 440.1 40 1

(S)-6- methyl-N- ((4-(trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- nicotinamide 440.1 41 1

(S)-6-oxo- N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin-2-yl)- methyl)-1,6- dihydro- pyridine- 3-carbox- amide 442.1 421

(S)-2- methoxy- N-((4- (trifluoro- methyl)- phenyl)- (3- (trifluoro-methyl)- pyridin-2- yl)methyl)- pyrimi- dine-5- carboxamide 457.1 43 1

(S)-N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin-2-yl)- methyl)-1H- pyrrolo[2,3- b]pyridine-3- carboxamide 465.044 1

(S)-2- hydroxy-N- ((4-(trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- isonicotin- amide 442.1 45 1

(S)-N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)- pyridin-2-yl)- methyl)-7H- pyrrolo[2,3- d]pyrimi- dine-5- carboxamide 466.1 46 2

(S)-N- ((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)- phenyl)-methyl)- 6- methoxy- nicotinamide 406.1 47 2

(S)-N- ((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)- phenyl)-methyl)- 2- methoxy- nicotinamide 406.1 48 1

(S)-3- methoxy- N-((4- (trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- isonicotin- amide 456.0 49 1

(S)-1- methyl-2- oxo-N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro-methyl)- pyridin- 2-yl)- methyl)-1,2- dihydro- pyridine- 4-carbox- amide456.0 50 1

(S)-1- methyl-6- oxo-N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro-methyl)- pyridin- 2-yl)- methyl)-1,6- dihydro- pyridine- 3-carbox- amide456.0 51 2

(S)-N- ((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)- phenyl)-methyl)- 6-oxo-1,6- dihydro- pyridine- 3-carbox- amide 392.1 52 2

(S)-N- ((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)- phenyl)-methyl)-6- methyl- nicotin- amide 390.2 53 2

(S)-N- ((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)- phenyl)-methyl)- 2- methyl- isonicotin- amide 390.2 54 2

(S)-N-((3- fluoro- pyridin-2- yl)(4- (trifluoro- methyl)- phenyl)-methyl)- 1H- pyrrolo[2,3- b]pyridine-3- carboxamide 415.1 55 1

(S)-4- methoxy- N-((4- (trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- nicotinamide 456.0 56 1

(S)-2-oxo- N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin-2- yl)- methyl)- indoline- 5-carbox- amide 480.0 57 1

(S)-2- methyl-N- ((4- (trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- pyrimi- dine-5- carboxamide 441.0 58 1

(S)-5- hydroxy-N- ((4- (trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- nicotinamide 442.1 59 1

(S)-2-oxo- N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin-2-yl)- methyl)-1,2- dihydro- pyridine- 3-carbox- amide 442.1 601

(S)-4- methyl-N- ((4-(trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- pyrimi- dine-5- carboxamide 441.0 61 1

(S)-4- hydroxy-N- ((4-(trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- pyrimi- dine-5- carboxamide 443.1 62 1

(S)-4- hydroxy-N- ((4-(trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- picolinamide 442.1 63 1

(S)-6-oxo- N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin-2-yl)- methyl)-1,6- dihydro- pyridine- 2-carbox- amide 442.1 641

(S)-5- hydroxy-N- ((4- (trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- picolinamide 442.1 65 1

6-oxo-N- ((S)-(4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin-2- yl)- methyl)- piperi- dine-3- carbox- amide 446.1 66 1

(S)-N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin-2- yl)- methyl)-1H- pyrrolo[2,3- b]pyridine-2- carboxamide 465.067 1

(S)-N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)- pyridin-2-yl)- methyl)-1H- pyrrolo[2,3- b]pyridine-6- carboxamide 465.0 68 2

(S)-N- ((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)- phenyl)-methyl)- 1-methyl- 6-oxo- 1,6-dihydro- pyridine-3- carboxamide 406.1 691

(S)-2- oxo-N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin- 2-yl)- methyl)- indoline- 6-carbox- amide 480.2 70 2

(S)-N- ((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)- phenyl)-methyl)- 2-oxo- indoline- 5- carbox- amide 430.1 71 2

(S)-N- ((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)- phenyl)-methyl)- 2-oxo indoline- 6- carbox- amide 430.1 72 2

(S)-N- ((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)- phenyl)-methyl)- 2-oxo-1,2- dihydro- pyridine- 3-carbox- amide 392.1 73 2

(S)-N- ((3-fluoro- pyridin-2- yl)(4- (trifluoro- methyl)- phenyl)-methyl)- 3-oxo-3,4- dihydro-2H- benzo[b]- [1,4]- oxa- zine-7-carboxamide 446.1 74 2

(S)-N- ((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)- phenyl)-methyl)- 4-(N-methyl- sulfamoyl)- benzamide 468.0 75 2

(S)-N-((3- fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)- phenyl)-methyl)- 2-oxo-3,4- dihydro-2H- benzo[b]- [1,4]oxa- zine-6- carboxamide446.1 76 2

(S)-N- ((3-fluoro- pyridin- 2-yl)(4- (tnfluoro- methyl)- phenyl)-methyl)- 2-oxo-2,3- dihydro- benzo[d]- oxazole- 5-carbox- amide 432.0 772

(S)-N- ((3-fluoro- (trifluoro- methyl)- phenyl)- methyl)- 3-oxo-3,4-dihydro-2H- benzo[b]- [1,4]oxa- zine-8- carboxamide 446.1 78 2

(S)-N- ((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)- phenyl)-methyl)- 2-oxo-2,3- dihydro- benzo[d]- oxazole- 6-carbox- amide 432.2 798

(S)-N- ((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methoxy)- phenyl)-methyl)- 2-oxo-2,3- dihydro- benzo[d]- oxazole- 5-carbox- amide 448.1 808

(S)-N- ((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methoxy)- phenyl)-methyl)- 2-oxo-2,3- dihydro- benzo[d]- oxazole- 6-carbox- amide 448.1 818

(S)-N- ((3-fluoro- (trifluoro- methoxy)- phenyl)- methyl)- 3-oxo-3,4-dihydro-2H- benzo[b]- [1,4]oxa- zine-7- carboxamide 462.0 82 44

(S)-N-((3- methyl- pyridin-2- yl)(4- (trifluoro- methyl)- phenyl)-methyl)- 6-oxo- 1,6-dihydro- pyridine-3- carboxamide 2,2,2- trifluoro-acetate 388.1 83 44

(S)-1- methyl-N- ((3- methyl- pyridin-2- yl)(4- (trifluoro- methyl)-phenyl)- methyl)- 6-oxo- 1,6-dihydro- pyridine-3- carboxamide 2,2,2-trifluoro- acetate 402.2 84 44

(S)-N-((3- methyl- pyridin-2- methyl)- phenyl)- yl)(4- (trifluoro-methyl)- 2-oxo- 2,3-dihydro- benzo[d]- oxazole- 5-carbox- amide 428.1 8544

(S)-N-((3- methyl- pyridin-2- yl)(4- (trifluoro- methyl)- phenyl)-methyl)- 3-oxo- 3,4- dihydro-2H- benzo[b]- [1,4]oxa- zine-7- carboxamide442.1 86 2

(S)-N- ((3-fluoro- pyridin-2- yl)(4- (trifluoro- methyl)- phenyl)-methyl)- imidazo- [1,2- a]pyridine- 7- carbox- amide 415.1 87 1

(S)-N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)- pyridin-2-yl)- methyl)- imidazo[1,2- a]pyridine- 7- carboxamide 465.0 88 8

(S)-N- ((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methoxy)- phenyl)-methyl)- imidazo[1,2- a]pyridine- 7- carboxamide 431.1 89 8

S)-N- ((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methoxy)- phenyl)-methyl)- imidazo[1,2- a]pyridine-6- carboxamide 2,2,2- trifluoro-acetate 431.1 90 8

(S)-N- ((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methoxy)- phenyl)-methyl)- 2-oxo- indoline-6- carbox- amide 446.1 91 8

(S)-N- ((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methoxy)- phenyl)-methyl)- 2-oxo- indoline-5- carbox- amide 446.1 92 47

(S)-6-oxo- N-((3- (prop-1- yn-1-yl)- pyridin-2- yl)(4- (trifluoro-methyl)- phenyl)- methyl)- 1,6-dihydro- pyridine-3- carboxamide 412.1 9347

(S)-N-((3- (prop- 1-yn-1-yl)- pyridin- 2-yl)(4- (trifluoro- methyl)-phenyl)- methyl)- quinoline-6- carboxamide 446.2 94 1

(S)-1,3- dioxo-N- ((4-(trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- isoindoline- 5- carboxamide 494.1 95 47

(S)-4- methoxy- N-((3- (prop-1- yn-1-yl)- pyridin- 2-yl)(4- (trifluoro-methyl)- phenyl)- methyl)- benzamide 2,2,2- trifluoro- acetate 425.2 9647

(S)-6- methoxy- N-((3- (prop-1- yn-1-yl)- pyridin- 2-yl)(4- (trifluoro-methyl)- phenyl)- methyl)- nicotinamide 426.2 97 47

(S)-N-((3- (prop- 1-yn-1-yl)- pyridin- 2-yl)(4- (trifluoro- methyl)-phenyl)- methyl)- quinoline-7- carboxamide 2,2,2- trifluoro- acetate446.2 98 47

(S)-N- ((3-(prop- 1-yn-1-yl)- pyridin- 2-yl)(4- (trifluoro- methyl)-phenyl)- methyl)- benzamide 395.1 99 1

(S)-1,3- dioxo-2- (pyridin- 2-yl)-N- ((4-(trifluoro- methyl)- phenyl)-(3-(trifluoro- methyl)- pydin-2- yl)methyl)- isoin- doline-5- carbox-amide 2,2,2- trifluoro- acetate 571.1 100 1

(S)-2- bromo-4- (((4- (trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- carbamoyl)- benzoic acid 549.0 101 48

(S)-N- ((3-((3- methyl- oxetan-3- yl)ethynyl)- pyridin-2- yl)(4-(trifluoro- methyl)- phenyl)- methyl)- quinoline-6- carboxamide 2,2,2-trifluoro- acetate 502.2 102 6

(S)-N- ((3-fluoro- 4-(trifluoro- methoxy)- phenyl)(3- fluoro- pyridin-2-yl)- methyl)- 6-oxo- 1,6-dihydro- pyridine-3- carboxamide 2,2,2-trifluoro- acetate 425.9 103 6

(S)-N-((3- fluoro- 4-(trifluoro- methoxy)- phenyl)(3- fluoro-pyridin-2-yl)- methyl)-1- methyl-6-oxo- 1,6-dihydro- pyridine-3-carboxamide 439.9 104 2 57

(S)-N-((3- fluoro- pyridin-2- yl)(4- (trifluoro- methyl)- phenyl)-methyl)- 2-oxo-1,2- dihydro- quinoline-6- carboxamide 441.8 105 2 58

(S)-N-((3- fluoro- pyridin-2- yl)(4- (trifluoro- methyl)- phenyl)-methyl)- 4-hydro- xyquino- line-7- carbox- amide 2,2,2- trifluoro-acetate 441.8 106 1 58

(S)-4- hydroxy-N- ((4-(trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- quinoline-7- carboxamide 2,2,2-trifluoro- acetate 491.6 107 7

(S)-N- ((3-fluoro- 4-(trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- benzamide 443.0 108 7

(S)-N- ((3-fluoro- 4-(trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- quinox- aline-6- carboxamide 494.9 109 155

(S)-4- hydroxy-N- ((4-(trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- quinoline-6- carboxamide 2,2,2-trifluoro- acetate 491.6 110 1 59

(S)-4- chloro-N- ((4-(trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- quinoline-7- carboxamide 2,2,2-trifluoro- acetate 509.6 111 7

(S)-N-((3- fluoro- 4-(trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- pyrazine-2- carboxamide 445.0 112 7

(S)-N-((3- fluoro- 4-(trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- picolinamide 443.9 113 2 56

(S)-4- chloro-N- ((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)-phenyl)- methyl)- quinoline-6- carboxamide 2,2,2- trifluoro- acetate459.6 114 2 55

(S)-N-((3- fluoro- pyridin-2- yl)(4- (trifluoro- methyl)- phenyl)-methyl)- 4-hydro- xyquinoline- 6- carboxamide 2,2,2- trifluoro- acetate441.8 115 29

(S)-N-((4- ethyl- phenyl)(3- (trifluoro- methyl)- pyridin- 2-yl)-methyl)- quinoline-7- carboxamide 436.1 116 1 56

(S)-4- chloro-N- ((4- (trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- quinoline-6- carboxamide 2,2,2-trifluoro- acetate 509.6 117 1

(S)-3-iodo- N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin- 2-yl)- methyl)- benzamide 550.5 118 1

(S)-2-iodo- N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin- 2-yl)- methyl)- benzamide 550.5 119 7

(S)-N- ((S)-(3- fluoro-4- (trifluoro- methyl)- phenyl)(3- (trifluoro-methyl)- pyridin- 2-yl)- methyl)- THF-2- carboxamide 437.0 120 2

(S)-4- chloro-N- ((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)-phenyl)- methyl)- quinoline-7- carboxamide 2,2,2- trifluoro- acetate459.6 121 1

(S)-4-(2- hydro- xypropan- 2-yl)- N-((4- (trifluoro- methyl)- phenyl)-(3- (trifluoro- methyl)- pyridin- 2- yl)methyl)- benzamide 483.0 122 1

(S)-4-iodo- N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin- 2-yl)- methyl)- benzamide 550.5 123 7

(R)-N- ((S)-(3- fluoro-4- (trifluoro- methyl)- phenyl)(3- (trifluoro-methyl)- pyridin- 2-yl)- methyl)- THF-2- carboxamide 437.0 124 27

(S)-N-((4- fluoro- phenyl)(3- (trifluoro- methyl)- pyridin- 2-yl)-methyl)-6- methoxy- nicotinamide 406.1 125 2 60

(S)-N- ((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)- phenyl)-methyl)- 2-oxo-1,2- dihydro- quino- line-7- carbox- amide 441.8 126 27

(S)-N-((4- fluoro- phenyl)(3- (trifluoro- methyl)- pyridin- 2-yl)-methyl)- benzamide 375.1 127 1

(S)-4- isopropyl- N-((4- (trifluoro- methyl)- phenyl)- (3- (trifluoro-methyl)- pyridin- 2-yl)- methyl)- benzamide 485.0 128 1

(S)-N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin-2-yl)- methyl)-1,8- naph- thyridine- 2- carbox- amide 2,2,2-trifluoro- acetate 476.9 129 7

(S)-N- ((3-fluoro- 4-(trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)meth- yl)-1,8- naph- thyridine-2- carbox- amide2,2,2- trifluoro- acetate 494.9 130 7

(S)-N- ((3-fluoro- 4-(trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- quinoline-6- carbox- amide bis (2,2,2-trifluoro- acetate) 494.0 131 7

(S)-N- ((3-fluoro- 4-(trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- quinoline-7- carboxamide 494.0 132 1

(S)-N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)- pyridin-2-yl)- methyl)- quinoline-7- carbox- amide 476.0 133 1

(S)-N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)- pyridin-2-yl)- methyl)- quinoline-6- carbox- amide 476.0 134 1

(S)-6- amino-N- ((4- (trifluoro- methyl)- phenyl)- (3- (trifluoro-methyl)- pyridin-2- yl)methyl)- nicotin- amide 441.0 135 1

(S)-6- chloro-N- ((4- (trifluoro- methyl)- phenyl)- (3- (trifluoro-methyl)- pyridin-2- yl)methyl)- nicotin- amide 460.0 136 1

(S)-2- amino-N- ((4- (trifluoro- methyl)- phenyl)- (3- (trifluoro-methyl)- pyridin-2- yl)methyl)- thiazole-4- carbox- amide 2,2,2-trifluoro- acetate 446.9 137 1

(S)-4- amino-2- methyl- N-((4- (trifluoro- methyl)- phenyl)(3-(trifluoro- methyl)- pyridin- 2-yl)- methyl)- pyrimidine-5- carboxamide456.0 138 1

(S)-N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)- pyridin-2-yl)- methyl)- thiophene- 2- carbox- amide 430.9 139 1

(S)-3- amino-N- ((4- (trifluoro- methyl)- phenyl)- (3- (trifluoro-methyl)- pyridin-2- yl)methyl)- isonicotin- amide 441.0 140 1

(S)- methyl 4- (((4- (trifluoro- methyl)- phenyl)- (3- (trifluoro-methyl)- pyridin-2- yl)methyl)- carbamoyl)- benzoate 482.9 141 1

(S)-4-(1H- tetrazol- 5-yl)-N- ((4- (trifluoro- methyl)- phenyl)- (3-(trifluoro- methyl)- pyridin- 2-yl)- methyl)- benzamide 493.0 142 1

tert-butyl 3-(((S)- (4- (trifluoro- methyl)- phenyl)- (3- (trifluoro-methyl)- pyridin-2- yl)methyl)- carbamoyl)- piper- idine-1- carboxylate554.0 (M + Na) 143 1

(S)-N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)- pyridin-2-yl)- methyl)-1H- pyrazole-4- carbox- amide 415.0 144 1

(S)-3- amino-N- ((4- (trifluoro- methyl)- phenyl)- (3- (trifluoro-methyl)- pyridin-2- yl)methyl)- picolin- amide 441.0 145 1

(S)-3-(4- methyl- thiazol-5- yl)-N-((4- (trifluoro- methyl)- phenyl)(3-(trifluoro- methyl)- pyridin- 2-yl)- methyl)- propan- amide 474.0 146 1

(S)-1- methyl-N- ((4-(tri- fluoro- methyl)- phenyl)- (3-(tri- fluoro-methyl)- pyridin-2- yl)meth- yl)-1H- imida- zole-2- carbox- amide 429.0147 1

(S)-N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)- pyridin-2-yl)- methyl)- pyr- imidine-5- carbox- amide 427.0 148 1

(S)-6- acetamido- N-((4- (trifluoro- methyl)- phenyl)- (3- (trifluoro-methyl)- pyridin-2- yl)methyl)- nicotin- amide 2,2,2- trifluoro- acetate482.9 149 1

(S)-5,7- dimethyl- N-((4- (trifluoro- methyl)- phenyl)- (3- (trifluoro-methyl)- pyridin-2- yl)methyl)- pyrazolo- [1,5- a]pyrim- idine-2-carbox- amide 494.0 150 1

(S)-6-oxo- N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin- 2-yl)- methyl)- 1,6- dihydro- pyrid- azine-3- carbox- amide443.0 151 1

(S)-5,7- dimethyl- N-((4- (trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- [1,2,4]- triazolo[1, 5-a]pyrim- idine-2-carboxamide 2,2,2- trifluoro- acetate 495.0 152 1

(S)-N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)- pyridin-2-yl)- methyl)- tetra- hydro-2H- pyran-4- carbox- amide 433.0 153 1

(S)-2-(5- methyl- 1H- pyrazol- 1-yl)- N-((4- (trifluoro- methyl)-phenyl)- (3- (trifluoro- methyl)- pyridin-2- yl)methyl)- acetamide 443.0154 1

(S)-2-(2- oxooxa- zolidin-3- yl)-N-((4- (trifluoro- methyl)- phenyl)(3-(trifluoro- methyl)- pyridin- 2-yl)- methyl)- acetamide 448.0 155 1

(S)-3-(1H- imidazol- 4-yl)-N- ((4-(tri- fluoro- methyl)- phenyl)- (3-(trifluoro- methyl)- pyridin-2- yl)methyl)- propan- amide 2,2,2-trifluoro- acetate 443.0 156 7

(S)-N-((3- fluoro- 4- (trifluoro- methyl)- phenyl)- (3- (trifluoro-methyl)- pyridin-2- yl)- methyl)-2- isobutyl- quinoline- 4-carbox- amidebis (2,2,2- trifluoro- acetate) 550.0 157 1

2-(THF- 3-yl)-N- ((S)-(4- (trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- acetamide 433.0 158 1

(S)-2-(1H- imidazol- 4-yl)-N- ((4- (trifluoro- methyl)- phenyl)- (3-(trifluoro- methyl)- pyridin-2- yl)methyl)- acetamide 429.0 159 1

(S)-3- amino-N- ((4- (trifluoro- methyl)- phenyl)- (3- (trifluoro-methyl)- pyridin-2- yl)methyl)- 1H- 1,2,4- triazole-5- carbox- amide431.0 160 1

(S)-2-(2- methyl- 1H- imidazol-1- yl)-N-((4- (trifluoro- methyl)-phenyl)(3- (trifluoro- methyl)- pyridin- 2-yl)- methyl)- acetamide 443.0161 1

(S)-2-(1H- imidazol- 1-yl)-N- ((4- (trifluoro- methyl)- phenyl)- (3-(trifluoro- methyl)- pyridin-2- yl)- methyl)- acetamide 2,2,2-trifluoro- acetate 428.9 162 1

2-aceta- mido-N- ((S)-(4- (trifluoro- methyl)- phenyl)- (3-(tri- fluoro-methriyl)- pyridin-2- yl)methyl)- propan- amide 434.0 163 1

5-oxo-N- ((S)-(4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin- 2-yl)- methyl)- pyrroli- dine-3- carbox- amide 432.0 164 1

(S)-2-(2- (trifluoro- methoxy)- (triphenyl)- N-((4- phenyl)(3-(trifluoro- methyl)- pyridin- 2-yl)- methyl)- acetamide 523.0 165 1

(S)-4- hydroxy-N- ((4- (trifluoro- methyl)- phenyl)- (3- (trifluoro-methyl)- pyridin-2- 441.0 166 2

(S)-N-((3- fluoro- pyridin-2- yl)(4- (trifluoro- methyl)- phenyl)-methyl)- 1H- indazole-6- carbox- amide 415.1 167 2

(S)-4- cyano-N- ((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)-phenyl)- methyl)- benzamide 400.1 168 1

(S)-3- cyano-N- ((4- (trifluoro- methyl)- phenyl)- (3- (trifluoro-methyl)- pyridin-2- yl)methyl)be 450.0 169 2

(S)-N-((3- fluoro- pyridin-2- yl)(4- (trifluoro- methyl)- phenyl)-methyl)- 2-methoxy- benzamide 405.2 170 2

(S)-N-((3- fluoro- pyridin-2- yl)(4- (trifluoro- methyl)- phenyl)-methyl)- quinox- aline-6- carbox- amide 427.1 171 1

(S)-4- methoxy- N-((4- (trifluoro- methyl)- phenyl)- (3- (trifluoro-methyl) pyridin-2- yl)methyl)- benzamide 455.1 172 2

(S)-N-((3- fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)- phenyl)-methyl)-4- methoxy- benzamide 405.0 173 2

(S)-N-((3- fluoro- pyridin-2- yl)(4- (trifluoro- methyl)- phenyl)-methyl)- 5-hydro- xypicolin- amide 392.1 174 1

(S)-4-(((4- (trifluoro- methyl)- phenyl)(3- trifluoro- methyl)- methyl)-carba- moyl)- phenyl acetate 483.0 175 1

(S)-N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)- pyridin-2-yl)- methyl)- 1H- indazole-6- carbox- amide 465.0 176 1

(S)-2- methoxy- N-((4- (trifluoro- methyl)- phenyl)- (3- (trifluoro-methyl)- pyridin-2- yl)methyl)- benzamide 455.1 177 2

(S)-N- ((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)- phenyl)-methyl)- 2-oxo-2,3- dihydro-1H- benzo[d]- imidazole- 5-carbox- amide431.1 178 1

(S)-N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)- pyridin-2-yl)- methyl)- isonicotin- amide 426.0 179 1

(S)-3-(((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin- 2-yl)- methyl)- carbamoyl)- benzoic acid 469.1 180 2

(S)-N-((3- fluoro- pyridin-2- yl)(4- (trifluoro- methyl)- phenyl)-methyl)- benzamide 375.2 181 1

(S)-4- cyano-N- ((4- (trifluoro- methyl)- phenyl)- (3- (trifluoro-methyl)- pyridin-2- yl)methyl)- benzamide 450.0 182 1

(S)-5- methyl-N- ((4- (trifluoro- methyl)- phenyl)- (3- (trifluoro-methyl)- pyridin-2- yl)methyl)- nicotin- amide 2,2,2- trifluoro- acetate440.1 183 1

(S)-4- fluoro-N- ((4- (trifluoro- methyl)- phenyl)- (3- (trifluoro-methyl)- pyridin-2- yl)methyl)- benzamide 443.1 184 2

(S)-3- cyano-N- ((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)-phenyl)- methyl)- benzamide 400.1 185 1

(S)-4- chloro-N- ((4- (trifluoro- methyl)- phenyl)- (3- (trifluoro-methyl)- pyridin-2- yl)methyl)- benzamide 459.0 186 1

(S)-3- (dimethyl- amino)- N-((4- (trifluoro- methyl)- phenyl)-(3-(trifluoro- methyl)- pyridin-2- yl)methyl)- benzamide 468.2 187 2

(S)-3- fluoro-N- ((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)-phenyl)- methyl)- benzamide 393.0 188 1

(S)-N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)- pyridin-2-yl)- methyl)- nicotin- amide 426.0 189 1

(S)- methyl 3- (((4- (trifluoro- methyl)- phenyl)- (3- (trifluoro-methyl)- pyridin-2- yl)methyl)- carbamoyl)- benzoate 483.0 190 1

(S)-4- methyl-N- ((4- (trifluoro- methyl)- phenyl)- (3- (trifluoro-methyl)- pyridin-2- yl)methyl)- oxazole-5- carbox- amide 430.1 191 1

(S)-3- methoxy- N-((4- (trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- benzamide 455.1 192 1

(S)-1- methyl-N- ((4-(trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- 1H- pyrazole-3- carboxamide 429.2 193 2a

N-((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)- phenyl)- methyl)-benzamide 375.0 194 2

(S)-N- ((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)- phenyl)-methyl)- picolinamide 376.1 195 44

(S)-N-((3- bromo- pyridin-2- yl)(4- (trifluoro- methyl)- phenyl)-methyl)- quinoline-7- carboxamide 486.0, 488.0 196 1

(S)-4- (dimethyl- amino)- N-((4- (trifluoro- methyl)- phenyl)-(3-(trifluoro- methyl)- pyridin-2- yl)methyl)- benzamide 468.1 197 1

(S)-2- cyano-N- ((4-(trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- benzamide 450.0 198 2

(S)-5- bromo-6- chloro- N-((3- fluoro- pyridin-2- yl)(4- (trifluoro-methyl)- phenyl)- methyl)- nicotinamide 488.0, 490.0 199 1

(S)-N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)- pyridin-2-yl)- methyl)- furan-3- carboxamide 415.1 200 2a

4-cyano- N-((3- fluoro- pyridin-2- yl)(4- (trifluoro- methyl)- phenyl)-methyl)- benzamide 400.1 201 54

(S)-6-oxo-N- (pyridin- 2-yl(4- (trifluoro- methyl)- phenyl)- methyl)-1,6-dihydro- pyridine-3- carboxamide 2,2,2- trifluoro- acetate 374.1 2022a

N-((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)- phenyl)- methyl)-quinox- aline-6- carboxamide 427.1 203 2

(S)-N-((3- fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)- phenyl)-methyl)- nicotinamide 376.1 204 2a

N-((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)- phenyl)- methyl)-quinoline-7- carboxamide 426.2 205 1

(S)-5- bromo-N- ((4-(trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- picolinamide 505.0, 507.0 206 1

(S)-6- cyano-N- ((4-(trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- nicotinamide 451.1 207 1

(S)-3-(((3- fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)- phenyl)-methyl)- carbamoyl)- benzoic acid 419.1 208 1

(S)-3- chloro-N- ((4-(trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- benzamide 460.1 209 2a

3-fluoro- N-((3- fluoro- pyridin-2- yl)(4- (trifluoro- methyl)- phenyl)-methyl)- benzamide 393.0 210 1

(S)-5- methoxy- N-((4- (trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- picolinamide 456.0 211 1

(S)-3- (trifluoro- methyl)- N-((4- (trifluoro- methyl)- phenyl)(3-(trifluoro- methyl)- pyridin-2-yl)- methyl)- benzamide 493.1 212 1

(S)-N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin-2-yl)- methyl)- pyridazine-4- carboxamide 427.1 213 2

(S)-N-((3- fluoro- pyridin-2- yl)(4- (trifluoro- methyl)- phenyl)-methyl)- 4-(methyl- sulfonamido)- benzamide 468.0 214 2a

N-((3-fluoro- pyridin-2- yl)(4- (trifluoro- methyl)- phenyl)- methyl)-3-methoxy- benzamide 405.0 215 1

(S)-1- methyl-N- ((4-(trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)meth- yl)-1H- indazole-3- carboxamide 479.1 216 2

(S)-N-((3- fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)- phenyl)-methyl)-3- (methyl- sulfonyl)- benzamide 453.0 217 2

(S)-N-((3- fluoro- pyridin- 2-yl)(4- (trifluoro- methyl)- phenyl)-methyl)-4- (methyl- sulfonyl)- benzamide 453.0 218 1

(S)-2- phenyl-N- ((4-(trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin- 2-yl)methyl)- acetamide 439.1 219 1

(S)-3- (trifluoro- methoxy)- N-((4- (trifluoro- methyl)- phenyl)(3-(trifluoro- methyl)- pyridin-2-yl)- methyl)- benzamide 509.1 220 1

(S)-N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin-2-yl)- methyl)- isoxazole-5- carboxamide 416.1 221 2a

N-((3-fluoro- pyridin-2- yl)(4- (trifluoro- methyl)- 4-methyl- oxazole-5-carbox- amide 380.1 222 1

(S)-N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin-2-yl)- methyl)- benzo[b]- thiophene- 2-carboxamide 481.1 223 1

3-oxo-N- ((S)-(4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin-2-yl)- methyl)- cyclohexane- carboxamide 445.1 224 1

(S)-3- methoxy- N-((4- (trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- propanamide 407.1 225 1

N-((S)-(4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin-2-yl)- methyl)- THF-3- carboxamide 419.1 226 1

(S)-5-(((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin-2-yl)- methyl)- carbamoyl)- nicotinic acid 470.1 227 1

(S)-3- fluoro-N- ((4-(trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- benzamide 443.1 228 1

(S)-N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin-2-yl)- methyl)- picolinamide 426.0 229 1

(S)-tert- butyl 3- (2-oxo-2- (((4- (trifluoro- methyl)- phenyl)(3-(trifluoro- methyl)- pyridin-2-yl)- methyl)- amino)- ethyl)-azetidine-1- carboxylate 462.0 (M- tBu) 230 1

(S)-N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin-2-yl)- methyl)- quinoline-3- carboxamide 476.1 231 1

(S)-4- (trifluoro- methoxy)- N-((4- (trifluoro- methyl)- phenyl)(3-(trifluoro- methyl)- pyridin-2-yl)- methyl)- benzamide 509.1 232 49

N-((S)- (3-((R)- 2,2- dimethyl- cyclopro- pyl)pyridin- 2-yl)-(4-(trifluoro- methyl)- phenyl)- methyl)- quinoline-7- carboxamide 476.0233 49

N-((S)- (3-((R)- 2,2- dimethyl- cyclopro- pyl)pyridin- 2-yl)-(4-(trifluoro- methyl)- phenyl)- methyl)- quinoline-6- carboxamide 476.0234 1

(S)-N- ((S)-(4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin-2-yl)- methyl)- THF-2- carboxamide 419.0 235 50

(S)-N- ((S)-(3- allyl- pyridin-2- yl)(4- (trifluoro- methyl)- phenyl)-methyl)-2- phenyl- propanamide. 425.0 236 51

(S)-N-((3- neopentyl- pyridin- 2-yl)(4- (trifluoro- methyl)- phenyl)-methyl)- quinoline-6- carboxamide 478.0 237 1

3,3,3- trifluoro-2- methoxy-2- phenyl-N- ((S)-(4- (trifluoro- methyl)-phenyl)(3- (trifluoro- methyl)- pyridin- 2-yl)- methyl)- propanamide537.0 238 1

(S)-2- (pyridin-3- yl)-N-((4- (trifluoro- methyl)- phenyl)(3-(trifluoro- methyl)- pyridin- 2-yl)- methyl)- acetamide 440.0 239 1

(S)-N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin-2- yl)- methyl)- benzo[d]- thiazole- 6-carbox- amide 481.9 240 1

(S)-2- methoxy-2- methyl- N-((4- (trifluoro- methyl)- phenyl)(3-(trifluoro- methyl)- pyridin- 2-yl)- methyl)- propan- amide 421.0 241 1

(1s,4R)-4- (hydro- xymethyl)- N- ((S)-(4- (trifluoro- methyl)- phenyl)-(3-(trifluoro- methyl)- pyridin-2- yl)methyl)- cyclohexane- carboxamide461.0 242 1

(S)-4- hydroxy-N- ((4- (trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- cyclo- hexanecar- boxamide 447.0 243 1

(S)-2,2- dimethyl- 3-oxo-3- (((4- (trifluoro- methyl)- phenyl)(3-(trifluoro- methyl)- pyridin- 2-yl)- methyl)- amino)- propanoic acid434.9 244 1

(S)-4-(((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin- 2-yl)- methyl)- carbamoyl)- cyclo- hexane- carboxylic acid475.0 245 1

(S)-3-oxo- N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)-pyridin- 2-yl)- methyl)-2,3- dihydro-1H- indene-5- carbox- amide 479.0246 1

(S)-3- benzoyl-N- ((4-(trifluoro- methyl)- phenyl)- (3-(trifluoro-methyl)- pyridin-2- yl)methyl)- benzamide 2,2,2- trifluoro- acetate529.0 247 52

N-((3,4- dichloro- phenyl)- (pyridin- 2-yl)methyl)- isoquino- line-6-carbox- amide bis- hydro- chloride 409.0, 410.0 248 35

(S)-N-((3- chloro- pyridin-2- yl)(4- (trifluoro- methyl)- phenyl)-methyl)- 6-oxo-1,6- dihydro- pyridine- 3-carbox- amide 2,2,2- trifluoro-acetate 407.7 249 35

(S)-N-((3- chloro- pyridin- 2-yl)(4- (trifluoro- methyl)- phenyl)-methyl)- 1-methyl- 6-oxo- 1,6-dihydro- pyridine-3- carbox- amide 2,2,2-trifluoro- acetate 421.9 250 36

(S)-N-((3,4- dichloro- phenyl)- (3-fluoro- pyridin- 2-yl)- methyl)-6-oxo-1,6- dihydro- pyridine-3- carboxamide 2,2,2- trifluoro- acetate391.7 251 36

(S)-N-((3,4- dichloro- phenyl)- (3-fluoro- pyridin- 2-yl)- methyl)-1-methyl-6-oxo- 1,6-dihydro- pyridine-3- carboxamide 2,2,2- trifluoro-acetate 405.8 252 8

(S)-N-((3- fluoro- pyridin-2- yl)(4- (trifluoro- methoxy)- phenyl)-methyl)- 1-methyl- 6-oxo- 1,6-dihydro- pyridine-3- carbox- amide 2,2,2-trifluoro- acetate 422.1 253 2

(S)-N-((3- fluoro- pyridin-2- yl)(4- (trifluoro- methyl)- phenyl)-methyl)- imidazo[1,2- a]pyridine-6- carboxamide 2,2,2- trifluoro-acetate 415.2 254 1

(S)-N-((4- (trifluoro- methyl)- phenyl)(3- (trifluoro- methyl)- pyridin-2-yl)- methyl)- imidazo[1,2- a]pyridine-6- carbox- amide 2,2,2-trifluoro- acetate 465.1 255 8

(S)-1- ethyl-N- ((3-fluoro- pyridin- 2-yl)(4- (trifluoro- methoxy)-phenyl)- methyl)- 6-oxo-1,6- dihydro- pyridine- 3-carbox- amide 436.1256 37

(S)-N-((2- bromo- phenyl)(4- (trifluoro- methyl)- phenyl)- methyl)-quinoline-6- carboxamide 2,2,2- trifluoro acetate 484.9, 486.9 257 38

(S)-N-((3- fluoro- 4-(trifluoro- methyl)- phenyl)- (2-(trifluoro-methyl)- phenyl)- methyl)- quinoline-6- carboxamide 493.0 258 39

(S)-N-((2,6- difluoro- phenyl)- (4-(trifluoro- methyl)- phenyl)-methyl)- 6-oxo- 1,6-dihydro- pyridine-3- carboxamide 408.8 259 40

(S)-N-((5- bromo- thiazol-4- yl)(4- (trifluoro- methyl)- phenyl)-methyl)- quinoline-6- carboxamide 2,2,2- trifluoro- acetate 491.8 493.9260 42

(S)-N-((4- (trifluoro- methyl)- phenyl)(4- (trifluoro- methyl)- pyridin-3-yl)- methyl)- quinoline-6- carbox- amide bis (2,2,2- trifluoro-acetate) 476.0 261 41

(S)-N- (3-phenyl- 1-(3- (trifluoro- methyl)- pyridin-2- yl)prop-2- yn-1-yl)- quinoline-7- carbox- amide 432.0

Additional Examples

Example 262(S)-6-(Dimethylamino)-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide

A glass microwave reaction vessel was charged with(S)-6-chloro-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide(50 mg, 0.109 mmol, example 135), DMF (1 mL), and 2 M diethylamine inTHF (0.054 mL, 0.109 mmol). The reaction mixture was stirred and heatedin a Biotage Initiator at 100° C. for 30 minutes. This was repeated at150° C. for 30 minutes at a time until LC-MS indicated completeconsumption of starting material. The reaction product was purified byreverse-phase preparative HPLC (Shimadzu) on a Phenomenex Gemini column(5 micron, C18, 110 Å, Axia, 100×30 mm) eluting at 45 mL/min with alinear gradient of 20% to 70% MeCN (0.1% TFA) in water (0.1% TFA) over20 minutes. The desired fractions were poured into 10% Na₂CO₃ andextracted with DCM (3×5 mL). The combined DCM layers were washed withbrine, dried over MgSO₄, and concentrated in vacuo to give the titlecompound as a white solid. ¹H NMR (CDCl₃, 300 MHz) δ ppm 8.86 (d, J=3.8Hz, 1H), 8.66 (d, J=2.2 Hz, 1H), 8.02 (d, J=7.9 Hz, 2H), 7.92 (dd,J=9.1, 2.5 Hz, 1H), 7.54 (s, 4H), 7.45 (dd, J=7.7, 4.4 Hz, 1H), 6.87 (d,J=7.9 Hz, 1H), 6.49 (d, J=9.2 Hz, 1H), 3.14 (s, 6H) MS (ESI pos. ion)m/z: 469.0 (M+H).

Example 263(S)-6-(Ethylamino)-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide

A glass microwave reaction vessel was charged with(S)-6-chloro-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide(50 mg, 0.109 mmol, example 135), THF (1 mL), and 2 Methylamine in THF(0.054 mL, 0.109 mmol). The reaction mixture was stirred and heated in aBiotage Initiator at 100° C. for 30 minutes. This was repeated at 150°C. for 30 minutes at a time until LC-MS indicated complete consumptionof starting material. The reaction product was purified by reverse-phasepreparative HPLC (Shimadzu) on a Phenomenex Gemini column (5 micron,C18, 110 Å, Axia, 100×30 mm) eluting at 45 mL/min with a linear gradientof 20% to 70% MeCN (0.1% TFA) in water (0.1% TFA) over 20 minutes togive(S)-6-(ethylamino)-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide2,2,2-trifluoroacetate as a white solid after lypholization. ¹H NMR(CDCl₃, 300 MHz) δ ppm 10.41 (br. s., 1H), 8.93 (d, J=4.1 Hz, 1H),8.12-8.39 (m, 3H), 8.05 (d, J=7.7 Hz, 1H), 7.41-7.63 (m, 5H), 6.71-6.86(m, 2H), 3.25-3.49 (m, 2H), 1.37 (t, J=7.3 Hz, 3H) MS (ESI pos. ion)m/z: 469.0 (M+H).

Example 264(S)—N-((3-Fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-2-methoxypyrimidine-5-carboxamide

To a solution of 2-methoxypyrimidine-5-carboxylic acid (80 mg, 0.519mmol), DIPEA (0.25 mL, 1.435 mmol) in toluene (3 mL) was added DPPA(0.19 mL, 0.882 mmol). The reaction was stirred at 80° C. for 2 hours.(S)-(3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methanaminedihydrochloride (167 mg, 0.487 mmol) was then added as a solid in oneportion. After 24 hours, the reaction was concentrated in vacuo and theresidue was adsorbed onto a plug of silica gel and chromatographedthrough a Redi-Sep® pre-packed silica gel column (12 g), eluting with 0%to 80% EtOAc in hexane, to provide the title compound as an off-whitesolid. ¹H NMR (DMSO-d6, 400 MHz) δ ppm 9.02 (d, J=4.7 Hz, 1H), 8.97 (d,J=8.6 Hz, 1H), 8.30 (d, J=7.8 Hz, 1H), 7.63-7.77 (m, 3H), 7.54 (d, J=8.2Hz, 2H), 7.39 (s, 1H), 7.01 (s, 1H), 6.66 (d, J=8.6 Hz, 1H), 3.93 (s,3H) MS (ESI pos. ion) m/z: 407.0 (M+H).

Example 265(S)-3-oxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)-pyridin-2-yl)methyl)isoindoline-5-carboxamide

To a 25 mL round bottom flask containing(S)-(4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)pyridin-2-yl)methanaminehydrochloride (Intermediate 1) (120 mg, 0.336 mmol) was added toluene (3mL). The resulting mixture was stirred at rt for 2 min. At this time,sodium carbonate (143 mg, 1.346 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.89 mg, 6.73 μmol),palladium (II) acetate (1.5 mg, 6.7 μmol) and6-bromo-2,3-dihydro-isoindol-1-one (71.3 mg, 0.336 mmol) were added tothe flask. The reaction vessel was flushed with argon and then leftunder 1.0 atm of carbon monoxide gas (from a lecture bottle, in hood).The flask was heated to 85° C. overnight, filtered though Celite® brandfilter agent, and eluted with EtOAc. Purification by reverse phase HPLC,and concentration of the containing fractions gave(S)-3-oxo-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)isoindoline-5-carboxamideas a yellow foamy solid. ¹H NMR (300 MHz, CDCl₃): δ ppm 8.92 (d, J=4.5Hz, 1H), 8.40 (d, J=7.7 Hz, 1H), 7.60-7.56 (m, 5H), 7.46-7.48 (m, 2H),6.90 (d, J=7.6 Hz, 1H), 4.54 (s, 2H). MS (ESI pos. ion) m/z: 480.1(M+H).

Example 266(S)-2-Hydroxy-N-((4-(trifluoromethyl)phenyl)(3-(trifluoro-methyl)pyridin-2-yl)methyl)pyrimidine-5-carboxamide

A 25 mL round-bottomed flask containing a suspension of(S)-2-methoxy-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)pyrimidine-5-carboxamide(Example 44) (0.094 g, 0.206 mmol) and sodium iodide, anhydrous (0.129g, 0.861 mmol) in anhydrous MeCN (3.5 mL) was treated withchlorotrimethylsilane, redistilled (0.130 mL, 1.028 mmol). The resultingsuspension was stirred at rt for 17.5 h. The reaction was concentratedon the rotary evaporator resulting in a gummy residue which was taken upin DCM (55 mL), H₂O (25 mL), and 10% aqueous sodium thiosulfate (20 mL).The resulting mixture was transferred to a separatory funnel and aftervigorous extraction the organic layer was separated, dried overanhydrous sodium sulfate, and concentrated to yield the product. Theproduct thus obtained was dissolved in DMSO/MeOH (1/1) (3.5 mL) andloaded on a Gibson HPLC system for purification using a MeCN/H₂O/0.1%TFA gradient and Phenomenex™ Gemini Axia-5μ C-18 column (150×30 mm). Thesolvent was removed from the pure fractions in the Genevac™ and theresulting product was dissolved in MeOH (3 mL), concentrated in theGenevac™, and dried under high vacuum to yield(S)-2-hydroxy-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)-methyl)pyrimidine-5-carboxamideas an amorphous white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.30 (d,J=7.6 Hz, 1H), 8.93 (d, J=3.9 Hz, 1H), 8.80 (s, 2H), 8.27 (dd, J=8.0,1.2 Hz, 1H), 7.75-7.70 (m, 2H), 7.64 (dd, J=7.9, 5.0 Hz, 1H), 7.56-7.50(m, 2H), 6.76 (d, J=7.6 Hz, 1H). MS (ESI pos. ion) m/z: 443.1 (M+H).

Example 267(S)-6-Oxo-N-((3-propylpyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-1,6-dihydropyridine-3-carboxamide

To a 250 mL round bottom flask containing(S)-6-oxo-N-((3-(prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1,6-dihydropyridine-3-carboxamide(Example 94) (50 mg, 0.122 mmol), were added EtOAc (50 mL) and MeOH (10mL). The resulting mixture then stirred at 23° C. for 2 min. At thistime, Pd/C (10%, 50 mg) was added and hydrogen was bubbled through thereaction vessel for 15 min, and the reaction was stirred under 1.0 atmhydrogen for 3 h, filtered through a pad of Celite™, eluted with EtOAc(150 mL), and concentrated to give (S)-tert-butyl((3-(prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoro-methyl)phenyl)methyl)carbamateas a foamy white solid. ¹H NMR (300 MHz, CDCl₃) δ ppm 13.03 (br. s.,1H), 8.68 (d, J=6.9 Hz, 1H), 8.53 (dd, J=1.5, 4.7 Hz, 1H), 8.09 (d,J=2.3 Hz, 1H), 7.95 (dd, J=2.6, 9.6 Hz, 1H), 7.62-7.41 (m, 5H),7.33-7.20 (m, 1H), 6.60 (d, J=9.5 Hz, 1H), 6.52 (d, J=6.9 Hz, 1H),2.73-2.57 (m, 1H), 2.56-2.39 (m, 1H), 1.87 (br. s., 1H), 1.68-1.48 (m,1H), 1.47-1.30 (m, 1H), 0.92 (t, J=7.3 Hz, 3H). MS (ESI pos. ion) m/z:416.2 (M+H).

Example 268(S)-2-Allyl-1,3-dioxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)isoindoline-5-carboxamide

To a 25 mL pear-shaped flask was added solid1,3-dioxo-1,3-dihydro-isobenzofuran-5-carboxylic acid (200 mg, 1.041mmol) and allylamine (234 μL, 3.12 mmol, 3 eq) via syringe. Toluene (2mL) and AcOH (1 mL) were added via syringes and the flask was refluxedfor 12 h. The flask was allowed to cool and then subjected to a DCM (75mL) and HCl (1N, 50 mL) work up. The aqueous layer was extracted withDCM (3×25 mL). The combined organic layers were washed with brine, driedwith sodium sulfate, filtered and concentrated. The residue thusobtained was azeotropically dried with toluene (2×, 5 mL) and heptane(2×5 mL). The resulting reside was placed on a high vacuum for 3 to give2-allyl-1,3-dioxoisoindoline-5-carboxylic acid.

2-Allyl-1,3-dioxoisoindoline-5-carboxylic acid was then coupled withIntermediate 1 using the general methods described above for the amidecoupling reaction (Table 2) to provide the title compound,(S)-2-allyl-1,3-dioxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)isoindoline-5-carboxamideas a white solid. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.93 (d, J=3.9 Hz, 1H),8.44 (d, J=7.6 Hz, 1H), 8.30-8.21 (m, 2H), 8.11-8.02 (m, 1H), 7.98-7.89(m, 1H), 7.64-7.46 (m, 5H), 6.88 (d, J=7.6 Hz, 1H), 5.99-5.75 (m, 1H),5.34-5.15 (m, 2H), 4.31 (d, J=5.7 Hz, 2H). MS (ESI pos. ion) m/z: 534.1(M+H).

Example 269(S)-1,3-Dioxo-2-propyl-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)isoindoline-5-carboxamide

To a 50 mL round bottom flask containing(S)-2-allyl-1,3-dioxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)isoindoline-5-carboxamide(Example 276) (160 mg, 0.300 mmol) was added EtOAc (15 mL). Theresulting mixture was stirred at 23° C. for 2 min. At this time, Pd/C(10%, 50 mg) was added and hydrogen was bubbled through the mixture for10 min. The reaction mixture was then left under 1 atm of hydrogen for 1h. The solid was filtered off on a pad of Celite™ and eluted with EtOAc(75 mL). The solvent was evaporated to give(S)-1,3-dioxo-2-propyl-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)isoindoline-5-carboxamideas a white solid. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.93 (d, J=4.1 Hz, 1H),8.42 (d, J=7.6 Hz, 1H), 8.30-8.19 (m, 2H), 8.11-8.01 (m, 1H), 7.91 (d,J=7.7 Hz, 1H), 7.64-7.45 (m, 5H), 6.88 (d, J=7.6 Hz, 1H), 3.68 (t, J=1.0Hz, 2H), 1.72 (sxt, J=7.4 Hz, 2H), 0.95 (t, J=7.5 Hz, 3H). MS (ESI pos.ion) m/z: 536.2 (M+H).

Example 270(S)-2-Methyl-1,3-dioxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)isoindoline-5-carboxamide

To a microwave vial was added1,3-dioxo-1,3-dihydroisobenzofuran-5-carboxylic acid (200 mg, 1.041mmol), THF (2 mL) and methylamine (2.0M THF, 2.0 mL). The flask wasirradiated in a microwave at 100° C. for 5 min. At this time, AcOH(glacial, 0.4 mL) and an additional portion of methylamine (2.0M THF,2.0 mL) were added, and the flask was placed in a the microwave at 100°C. for 2 h. The flask was allowed to cool and then azeotropically dried(toluene, 3×5 mL). The flask was placed under a high vacuum for 12 h toprovide 2-methyl-1,3-dioxoisoindoline-5-carboxylic acid which was useddirectly in the amide coupling reaction without further purification.

2-Allyl-1,3-dioxoisoindoline-5-carboxylic acid was then coupled withIntermediate 1 using the general methods described above for the amidecoupling reaction (Table 2) to provide the title compound,(S)-2-methyl-1,3-dioxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)isoindoline-5-carboxamideas a white solid. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.95 (d, J=4.7 Hz, 1H),8.44 (d, J=7.5 Hz, 1H), 8.31-8.20 (m, 2H), 8.08 (d, J=8.2 Hz, 1H), 7.93(d, J=7.6 Hz, 1H), 7.65-7.42 (m, 5H), 6.88 (d, J=7.6 Hz, 1H), 3.22 (s,3H). MS (ESI pos. ion) m/z: 508.1 (M+H).

Example 271(S)-1-Oxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)-pyridin-2-yl)methyl)isoindoline-5-carboxamide

Step 1. Methyl 1-oxoisoindoline-5-carboxylate

To a 25 mL round bottom flask containing5-bromo-2,3-dihydro-isoindol-1-one (500 mg, 2.36 mmol), was added TEA.The resulting mixture was then stirred at 23° C. for 2 min. At thistime, MeOH (954 μL, 23.58 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (54.6 mg, 0.094mmol)(Xantphos) and palladium(II) acetate (10.59 mg, 0.047 mmol) wereadded to the flask. The reaction mixture was then flushed with argon andthen with carbon monoxide. The flask was fitted with a rubber septa anda balloon of carbon monoxide was inserted through septa. The flask wasstirred at 70° C. overnight under carbon monoxide, allowed to cool,diluted with EtOAc (50 mL) and filtered through Celite™ eluting withEtOAc (300 mL). The solid remaining on the Celite™ pad was washed withDCM (200 mL) and DCM/MeOH (10:1)(150 mL) and the filtrates concentratedto give a pale green solid (800 mg). A portion of this material wastaken on to the next reaction with no further purification.

Step 2. 1-Oxoisoindoline-5-carboxylic Acid

To a 100 mL round bottom flask containing methyl1-oxoisoindoline-5-carboxylate (200 mg, 1.046 mmol) was added THF (6 mL)and H₂O (2 mL) the mixture was stirred at 23° C. for 2 min. At thistime, lithium hydroxide monohydrate (87 μL, 3.14 mmol) was added and theflask was gently heated on aluminum block for 5 min. The solid went intosolution and LC/MS showed product formation. The contents of thereaction were poured into HCl (1 M, 15 mL) and extracted with DCM (15mL). An emulsion formed, the layers separated, and a white solid formedat the boundary of the layers and stuck to the separatory funnel. Thismaterial was collected, dissolved in MeOH, and concentrated. Afterdrying under high vacuum for 2 h, the 1-oxoisoindoline-5-carboxylic acidthus obtained was taken on directly to the next reaction without furtherpurification.

Step 3.(S)-1-Oxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)isoindoline-5-carboxamide

1-Oxoisoindoline-5-carboxylic acid was then coupled with Intermediate 1using the general methods described above for the amide couplingreaction (Table 2) to provide the title compound,(S)-1-oxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)isoindoline-5-carboxamide,as a white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.92 (d, J=4.7 Hz, 1H),8.36 (d, J=7.4 Hz, 1H), 8.09-7.99 (m, 2H), 7.97-7.88 (m, 2H), 7.65-7.53(m, 5H), 7.51 (dd, J=4.9, 7.8 Hz, 1H), 6.90 (d, J=7.6 Hz, 1H), 4.54 (s,2H). MS (ESI pos. ion) m/z: 480.2 (M+H).

Example 272(S)-6-(((3-Fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)-methyl)carbamoyl)nicotinicAcid

To a 150 mL round bottom flask containing (S)-methyl6-(((3-fluoro-pyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)carbamoyl)nicotinate(250 mg, 0.556 mmol) (prepared using the general coupling procedureTable 2 with Intermediate 1 and 5-((methylperoxy)carbonyl)picolinicacid) were added THF (6 mL) and H₂O (2 mL). The resulting mixture wasstirred at 23° C. for 2 min. At this time, lithium hydroxide monohydrate(61.8 μL, 2.23 mmol) was added and the reaction was stirred for 3 h. Thebulk of the solvent was evaporated to give a foamy solid that oiled out.The residue was dissolved in AcOH (8 mL). The solution was purified byreverse phase HPLC and the product-containing fractions concentrated togive the title compound as a white solid. ¹H NMR (300 MHz, CDCl₃) δ ppm9.65 (d, J=7.3 Hz, 1H), 9.21 (s, 1H), 8.61 (d, J=4.1 Hz, 1H), 8.42 (d,J=7.3 Hz, 1H), 8.24 (d, J=8.0 Hz, 1H), 7.63-7.42 (m, 3H), 7.39 (dd,J=4.2, 8.3 Hz, 1H), 7.20 (d, J=7.9 Hz, 2H), 6.74 (d, J=6.7 Hz, 1H). MS(ESI pos. ion) m/z: 436.2 (M+H).

Example 273(S)—N²-((3-Fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)-methyl)-N⁵-methylpyridine-2,5-dicarboxamide2,2,2-trifluoroacetate

To a 50 mL round bottom flask containing(S)-6-(((3-fluoropyridin-2-yl)-(4-(trifluoromethyl)phenyl)methyl)carbamoyl)nicotinicacid (Example 280) (86 mg, 0.205 mmol) was added DMF (3 mL). Theresulting mixture was stirred at 23° C. for 2 min. At this time, DIPEA(143 μL, 0.820 mmol), methylamine (2.0 M in THF, 103 μL, 0.205 mmol) andthen HATU (78 mg, 0.205 mmol) were added to the flask. The reaction wasstirred for 1 h and then directly purified by reverse phase HPLC. Thepure fractions were concentrated to give the title compound as a whitesolid. ¹H NMR (300 MHz, CDCl₃) δ ppm 9.85 (d, J=7.2 Hz, 1H), 9.00 (s,1H), 8.55 (d, J=4.4 Hz, 1H), 8.20 (s, 2H), 7.60 (s, 4H), 7.52 (t, J=8.7Hz, 1H), 7.45-7.34 (m, 1H), 6.74 (d, J=7.3 Hz, 1H), 6.55 (br. s., 1H),3.07 (d, J=4.5 Hz, 3H). MS (ESI pos. ion) m/z: 433.1 (M+H).

Example 274(S)—N-((4-(Trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-1,2,3,4-tetrahydroquinoline-7-carboxamide

To a solution of(S)—N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)-pyridin-2-yl)methyl)quinoline-7-carboxamide(Example 132) (0.500 g, 1.052 mmol) in MeOH (6 mL) was added palladiumhydroxide, (20 wt % Pd (dry basis) on carbon, wet, degussa type) (0.148g, 1.052 mmol). The resulting mixture was then stirred at rt under H₂overnight. The resulting mixture was filtered through Celite® brandfilter agent and the Celite® filter agent was washed with MeOH (2×3 mL).The combined filtrates were concentrated and the mixture was dissolvedin DMSO (3 mL). The mixture was purified by preparative HPLC (0%-100%MeCN 0.1% TFA/H₂O 0.1% TFA) to give the desired product, which wasdissolved in MeOH (2 mL). The solution was washed through PL_HCO₃ MP-SPEresin and the resin was washed with MeOH (2×2 mL). The combinedfiltrates were concentrated and dried in vacuo to give the titlecompound as a yellow solid. ¹H NMR (400 MHz, MeOH) δ ppm 8.94 (d, J=4.1Hz, 1H), 8.22 (dd, J=8.0, 1.0 Hz, 1H), 7.50-7.70 (m, 5H), 6.94-7.02 (m,3H), 6.90 (s, 1H), 3.24-3.31 (m, 2H), 2.78 (t, J=6.4 Hz, 2H), 1.86-1.99(m, 2H). MS (ESI pos. ion) m/z: 480.2 (M+H).

Example 275(S)-5-Cyano-N-((4-(trifluoromethyl)phenyl)(3-(trifluoro-methyl)pyridin-2-yl)methyl)picolinamide

To a solution of(S)-5-bromo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoro-methyl)pyridin-2-yl)methyl)picolinamide(Example 205) (0.100 g, 0.198 mmol) in DMF (1.3 mL) was added zinccyanide (0.050 mL, 0.793 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.023 g, 0.020 mmol). Theresulting mixture was subjected to a microwave irradiation at 140° C.for 20 min. The mixture was then purified by preparative HPLC (0%-100%MeCN 0.1% TFA/H₂O 0.1% TFA) to give the title compound as a white solid.¹H NMR (400 MHz, MeOH) δ ppm 8.95-9.06 (m, 2H), 8.39 (dd, J=8.1, 2.1 Hz,1H), 8.21-8.32 (m, 2H), 7.57-7.70 (m, 5H), 6.89 (s, 1H). MS (ESI pos.ion) m/z: 451.1 (M+H).

Example 276(S)—N-(Pyridin-2-yl(4-(trifluoromethyl)phenyl)methyl)-1,2,3,4-tetrahydroquinoline-7-carboxamide

To a solution of(S)—N-((3-bromopyridin-2-yl)(4-(trifluoromethyl)phenyl)-methyl)quinoline-7-carboxamide(Example 195) (0.130 g, 0.267 mmol) in MeOH (0.8 mL) and EtOAc (0.800mL) was added palladium hydroxide, (20 wt % Pd (dry basis) on carbon,wet) (0.019 g, 0.134 mmol). The resulting mixture was then stirred at rtunder H₂ (balloon) overnight. The mixture was then filtered throughCelite® brand filter agent and the Celite® filter agent was washed withMeOH (2×3 mL). The combined filtrates were concentrated, and the residuewas dissolved in MeOH (1 mL). The solution was purified by preparativeHPLC (0%-100% MeCN 0.1% TFA/H₂O 0.1% TFA) to give the desired product,which was dissolved in MeOH (1 mL). The solution was washed throughPL_HCO₃ MP-SPE and the resin was washed with MeOH (2×1 mL). The combinedfiltrates were concentrated and dried in vacuo to give the titlecompound as a yellow solid. ¹H NMR (400 MHz, MeOH) δ ppm 8.59 (d, J=4.7Hz, 1H), 7.84 (td, J=7.7, 1.6 Hz, 1H), 7.61-7.68 (m, 2H), 7.54-7.60 (m,2H), 7.49 (d, J=7.8 Hz, 1H), 7.36 (dd, J=7.5, 5.0 Hz, 1H), 6.93-7.07 (m,3H), 6.44 (s, 1H), 3.25-3.30 (m, 2H), 2.78 (t, J=6.4 Hz, 2H), 1.91 (dt,J=11.6, 6.0 Hz, 2H). MS (ESI pos. ion) m/z: 412.1 (M+H).

Example 277(S)-5-Cyano-N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide

Step 1.(S)-5-Bromo-N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)-methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide

To a solution of HATU (0.332 g, 0.874 mmol) in DCM (2 mL) was added5-bromo-6-hydroxynicotinic acid (0.191 g, 0.874 mmol) and DIPEA (0.406mL, 2.331 mmol). The resulting mixture was then stirred at rt for 5 min,then (S)-(3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methanaminehydrochloride (Intermediate 2) (0.200 g, 0.583 mmol) was added. Themixture was then stirred at rt overnight. The mixture was purified bysilica gel column chromatography using an ISCO instrument (0%-100%EtOAc/hexane) to give the title compound as a brown oil.

Step 2.(S)-5-Cyano-N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)-methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide

To a solution of(S)-5-bromo-N-((3-fluoropyridin-2-yl)(4-(trifluoro-methyl)phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide(0.080 g, 0.170 mmol) in DMF (0.5 mL) was added zinc(II) cyanide (0.043mL, 0.681 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.020 g,0.017 mmol). The resulting mixture was then subjected to a microwaveirradiation at 130° C. for 30 min. Then, the mixture was purified bypreparative HPLC (0%-100% MeCN 0.1% TFA/H₂O 0.1% TFA) to give the titlecompound as a white solid. ¹H NMR (400 MHz, MeOH) δ ppm 8.63 (d, J=2.5Hz, 1H), 8.51 (d, J=4.7 Hz, 1H), 8.42 (d, J=2.5 Hz, 1H), 7.55-7.73 (m,6H), 7.47 (dt, J=8.5, 4.4 Hz, 1H), 6.75 (s, 1H). MS (ESI pos. ion) m/z:417.0 (M+H).

Example 278(S)—N-((3-Cyanopyridin-2-yl)(4-(trifluoromethyl)phenyl)-methyl)quinoline-7-carboxamide

To a microwave vial were added(S)—N-((3-bromopyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)quinoline-7-carboxamide(Example 195) (0.100 g, 0.206 mmol), zinc cyanide (0.026 mL, 0.411mmol), tetrakis(triphenylphosphine)-palladium(0) (0.024 g, 0.021 mmol),and DMF (1.3 mL). The resulting mixture was then subjected to microwaveirradiation at 130° C. for 30 min. EtOAc (10 mL) and H₂O (10 mL) werethen added, and the resulting mixture was stirred at rt for 5 min. Theorganic layer was collected, dried over MgSO₄ and concentrated. Theresidue was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H₂O0.1% TFA) to give the desired product, which was dissolved in MeOH (1mL). The solution was washed through PL_HCO₃ MP-SPE resin and the resinwas washed with MeOH (2×1 mL). The combined filtrates were concentratedand dried in vacuo to give the title compound as a yellow solid. ¹H NMR(400 MHz, MeOH) δ ppm 8.98 (dd, J=4.1, 1.6 Hz, 1H), 8.93 (dd, J=4.9, 1.6Hz, 1H), 8.60 (s, 1H), 8.46 (d, J=8.4 Hz, 1H), 8.25 (dd, J=7.8, 1.6 Hz,1H), 8.08 (s, 2H), 7.70-7.81 (m, 4H), 7.66 (dd, J=8.4, 4.3 Hz, 1H), 7.58(dd, J=7.8, 4.9 Hz, 1H), 6.91 (s, 1H). MS (ESI pos. ion) m/z: 433.1(M+H).

Example 279(S)-2-((6-(((3-Fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)-methyl)carbamoyl)pyridin-3-yl)oxy)aceticAcid

To a solution of(S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)-methyl)-5-hydroxypicolinamide(Example 173) (0.145 g, 0.371 mmol) in DCM (2 mL) and DMF (0.2 mL) wereadded bromoacetic acid t-butyl ester (0.072 mL, 0.445 mmol) and cesiumcarbonate (0.241 g, 0.741 mmol). The resulting mixture was then stirredat rt for 2 h. Then, the mixture was filtered and the solid was washedwith DCM (1×1 mL) and MeOH (1×1 mL). The combined filtrates wereconcentrated and dried to give the desired product, which was usedwithout further purification in the next step.

To a solution of the (S)-tert-butyl2-((6-(((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamoyl)pyridin-3-yl)oxy)acetatefrom above in DCM (0.5 mL), was added TFA (0.550 mL, 7.40 mmol). Theresulting mixture was then stirred at rt for 1 h. The mixture was thenconcentrated and MeOH (1 mL) was added. The mixture was purified bypreparative HPLC (0%-100% MeCN 0.1% TFA/H₂O 0.1% TFA) to give the titlecompound as a white solid. ¹H NMR (400 MHz, MeOH) δ ppm 8.55 (d, J=4.7Hz, 1H), 8.42 (d, J=2.5 Hz, 1H), 8.08 (d, J=8.8 Hz, 1H), 7.59-7.72 (m,5H), 7.42-7.55 (m, 2H), 6.68 (d, J=1.6 Hz, 1H), 4.89 (s, 2H). MS (ESIpos. ion) m/z: 450.2 (M+H).

Example 280(S)-6-(((3-Fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)-methyl)carbamoyl)nicotinicAcid

To a solution of 5-(methoxycarbonyl)picolinic acid (101 mg, 0.558 mmol)in DCM (4 mL) was added HATU (217 mg, 0.571 mmol) and DIPEA (0.20 mL,1.148 mmol). After stirring for 30 min at rt, the reaction was treatedwith (S)-(3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methanaminehydrochloride (Intermediate 2) (125 mg, 0.364 mmol). After 16 h, thereaction was concentrated in vacuo and then taken up in THF (3 mL), MeOH(1 mL), and 1M LiOH (1 mL). The resulting mixture was stirred at rt for2 h. The reaction mixture was concentrated in vacuo, acidified with 1NHCl and extracted with EtOAc (3×5 mL). The combined EtOAc layers wereconcentrated in vacuo and chromatographed through a Redi-Sep® pre-packedsilica gel column (4 g), eluting with 0% to 100% EtOAc in hexane, toprovide the title compound as an off-white solid. ¹H NMR (CDCl₃:CD₃OD,300 MHz) δ ppm 9.21 (d, J=1.5 Hz, 1H), 8.47 (d, J=4.7 Hz, 1H), 8.39 (dd,J=8.0, 1.9 Hz, 1H), 8.14 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.5 Hz, 2H), 7.50(d, J=8.6 Hz, 2H), 7.42 (t, J=9.5 Hz, 1H), 7.27-7.32 (m, 1H), 6.63 (s,1H). MS (ESI pos. ion) m/z: 419.9 (M+H).

Example 281(S)-6-(((4-(Trifluoromethyl)phenyl)(3-(trifluoromethyl)-pyridin-2-yl)methyl)carbamoyl)nicotinicAcid

To a solution of 5-(methoxycarbonyl)picolinic acid (70.7 mg, 0.390 mmol)and DIPEA (0.20 mL, 1.148 mmol) in DMF (2 mL) were added HATU (223 mg,0.586 mmol) and(S)-(4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)-methanaminehydrochloride (Intermediate 1) (125 mg, 0.390 mmol). The resultingmixture was stirred at rt 16 h. The mixture was then diluted with THF(10 mL), MeOH (3 mL), and 1M LiOH (2 mL). After a further 16 h, thereaction was concentrated in vacuo, taken up in a minimum of DMF andpurified by reverse-phase preparative HPLC (Shimadzu) on a PhenomenexGemini™ column (5 micron, C18, 110 Å, Axia, 100×30 mm) eluting at 45mL/min with a linear gradient of 20% to 90% MeCN (0.1% TFA) in H₂O (0.1%TFA) over 10 minutes to give the title compound as a white solid afterlypholization. ¹H NMR (CDCl₃, 300 MHz) δ ppm 9.74 (d, J=8.2 Hz, 1H),9.25 (s, 1H), 8.97 (d, J=4.0 Hz, 1H), 8.47 (dd, J=8.0, 2.1 Hz, 1H), 8.26(d, J=8.8 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.61 (d, J=8.5 Hz, 2H), 7.55(d, J=8.5 Hz, 2H), 7.46 (dd, J=7.5, 5.0 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H).MS (ESI pos. ion) m/z: 469.9 (M+H).

Example 282(S)—N²-((3-Fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)-methyl)pyridine-2,5-dicarboxamide

To a solution of 5-cyanopicolinic acid (93 mg, 0.628 mmol) in DCM (6 mL)were added DIPEA (0.3 mL, 1.722 mmol) and HATU (247 mg, 0.650 mmol). Thesolution was stirred at rt. After 20 minutes, the reaction was treatedwith (S)-(3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methanaminehydrochloride (Intermediate 2) (115 mg, 0.426 mmol). After stirring for16 h, the reaction was poured into H₂O (20 mL). The aqueous layer wasback-extracted with DCM (10 mL). The combined DCM layers wereconcentrated in vacuo and taken up in 3 mL of concentrated sulfuricacid. The mixture was stirred at rt for 4 hours and then was poured into75 g of ice. After stirring for 1 hour, the reaction was filtered, andthe solids were rinsed with H₂O. The solids were then taken up in EtOAc(30 mL) and washed with saturated aqueous NaHCO₃. The EtOAc layer wasconcentrated in vacuo to give the title compound as an off-white solid.¹H NMR (CDCl₃, 300 MHz) δ ppm 9.93 (d, J=7.5 Hz, 1H), 9.07 (s, 1H), 8.53(d, J=4.7 Hz, 1H), 8.23-8.27 (m, 2H), 7.61 (d, J=8.3 Hz, 2H), 7.55 (d,J=8.3 Hz, 2H), 7.42 (td, J=8.2, 1.3 Hz, 1H), 7.27-7.35 (m, 1H), 6.69(dd, J=7.8, 1.9 Hz, 1H), 5.92 (br s, 2H). MS (ESI pos. ion) m/z: 419.9(M+H).

Example 283(S)-4-(((4-(Trifluoromethyl)phenyl)(3-(trifluoromethyl)-pyridin-2-yl)methyl)carbamoyl)benzoicAcid

To a solution of (S)-methyl4-(((4-(trifluoromethyl)phenyl)(3-(trifluoro-methyl)pyridin-2-yl)methyl)carbamoyl)benzoate(135 mg, 0.280 mmol, Example 140) and THF (7 mL):MeOH (3 mL) was added1M LiOH (1 mL, 1.000 mmol). After 2 h, the reaction was concentrated invacuo. The off-white solid was taken up in a minimum of DCM and elutedthrough a Redi-Sep® pre-packed silica gel column (4 g) with EtOAc toprovide the title compound as a white solid. ¹H NMR (CD₃OD, 300 MHz) δppm 8.91 (d, J=4.8 Hz, 1H), 8.18 (d, J=7.9 Hz, 1H), 8.03 (d, J=8.3 Hz,2H), 7.85 (d, J=8.2 Hz, 2H), 7.53-7.66 (m, 5H), 6.93 (s, 1H). MS (ESIpos. ion) m/z: 469.0 (M+H).

Example 284(S)-3-(Pyridin-2-yl)-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)propanamide

To a solution of 3-(pyridin-2-yl)propanoic acid (89 mg, 0.586 mmol,Oakwood) and DCM (4 mL) were added CDI (95 mg, 0.586 mmol) and DIPEA(0.20 mL, 1.148 mmol). After 0.5 hours, the reaction was treated with asolution of(S)-(4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methanaminehydrochloride (Intermediate 1) (125 mg, 0.390 mmol) in DCM (1.5 mL). Thesolution was stirred at rt. After 4 days, the resulting product wasadsorbed onto a plug of silica gel and chromatographed through aRedi-Sep® pre-packed silica gel column (4 g), eluting with 0% to 60%EtOAc in hexane, to provide the title compound as a colorless oil. ¹HNMR (CDCl₃, 300 MHz) δ ppm 8.79 (d, J=3.8 Hz, 1H), 8.45 (d, J=4.8 Hz,1H), 7.96 (d, J=7.9 Hz, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.44-7.52 (m, 3H),7.34-7.43 (m, 3H), 7.03-7.12 (m, 2H), 6.63 (d, J=8.0 Hz, 1H), 3.11 (td,J=6.7 & 2.5 Hz, 2H), 2.74 (td, J=7.2 & 2.5 Hz, 2H). MS (ESI pos. ion)m/z: 454.0 (M+H).

Example 285(S)-5-(((4-(Trifluoromethyl)phenyl)(3-(trifluoromethyl)-pyridin-2-yl)methyl)carbamoyl)picolinicAcid 2,2,2-trifluoroacetate

To a solution of 6-(methoxycarbonyl)nicotinic acid (58.4 mg, 0.322 mmol)and DIPEA (0.20 mL, 1.148 mmol) in DMF (2 mL) were added HATU (178 mg,0.468 mmol) and(S)-(4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)-methanaminehydrochloride (Intermediate 1) (100 mg, 0.312 mmol). The solution wasstirred at rt for 2 h. The solution was then diluted with THF (10 mL),MeOH (3 mL), and 1M LiOH (2 mL). After a further 16 h, the reaction wasconcentrated in vacuo, taken up in a minimum of DMF and purified byreverse-phase preparative HPLC (Shimadzu) on a Phenomenex Gemini™ column(5 micron, C18, 110 Å, Axia, 100×30 mm) eluting at 45 mL/min with alinear gradient of 20% to 90% MeCN (0.1% TFA) in H₂O (0.1% TFA) over 10minutes to the title compound as a yellow solid. ¹H NMR (CDCl₃, 300 MHz)δ ppm 9.14 (s, 1H), 8.94 (d, J=4.4 Hz, 1H), 8.64 (d, J=7.2 Hz, 1H), 8.41(d, J=8.0 Hz, 1H), 8.25 (d, J=7.9 Hz, 1H), 8.13 (d, J=7.9 Hz, 1H),7.46-7.63 (m, 5H), 6.88 (d, J=7.0 Hz, 1H). MS (ESI pos. ion) m/z: 469.9(M+H).

Example 286(S)—N-((3-(tert-Butyl)pyridin-2-yl)(4-(trifluoromethyl)phenyl)-methyl)quinoline-7-carboxamide2,2,2-trifluoroacetate

To a −78° C. solution of(S)—N-((3-bromopyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)quinoline-7-carboxamide(97 mg, 0.199 mmol, Example 195) and THF (5 mL) was addedtert-butyllithium (1.7M in pentane, 0.35 mL, 0.595 mmol) dropwise. After30 seconds, the reaction was treated with acetone. After 1 min, LC-MSshows a new peak with m/z=466 (MH+), ˜20% conversion. The reaction wastreated with more tert-butyllithium (0.1 mL) and allowed to slowly warmto rt. Another reaction was setup at the same scale and as describedabove. The reactions were combined and concentrated in vacuo. Theresidue was taken up in MeOH (3 mL) and purified by reverse-phasepreparative HPLC (Shimadzu) on a Phenomenex Gemini™ column (10 micron,C18, 110 Å, Axia, 100×50 mm) eluting at 90 mL/min with a linear gradientof 20% to 90% MeCN (0.1% TFA) in H₂O (0.1% TFA) over 10 minutes to givethe title compound as an off-white solid after lypholization. ¹H NMR(CDCl₃, 300 MHz) δ ppm 9.85 (s, 1H), 9.44 (d, J=7.3 Hz, 1H), 8.79 (d,J=4.2 Hz, 1H), 8.64 (d, J=8.8 Hz, 1H), 8.37 (d, J=8.5 Hz, 1H), 8.05 (d,J=8.5 Hz, 1H), 7.98 (t, J=7.3 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.69-7.82(m, 3H), 7.61 (d, J=8.2 Hz, 1H), 7.45-7.53 (m, 1H), 6.76 (d, J=7.3 Hz,1H), 1.67 (s, 9H). MS (ESI pos. ion) m/z: 464.0 (M+H).

TABLE 3 Additional diarylmethanamines prepared analogous to Scheme 5 and6 (Intermediates 61-97). Unless otherwise stated, all amines in thistable are hydrochloride salts. Aryl Halide or Mol. Inter- Grignard inFormula mediate Method Step 2 Structure Name (Mol. Wt.) 61 A

(S)-(3,6- difluoropyridin- 2-yl)(3-fluoro- 4-(trifluoro- methoxy)phenyl)methanamine C₁₃H₈F₆N₂O (322.21) 62 A

(S)-(3-fluoro-4- (trifluoromethoxy) phenyl)(5- fluoropyridin- 2-yl)methanamine C₁₃H₉F₅N₂O (304.22) 63 A

(S)-(3-fluoro-4- (trifluoromethoxy) phenyl) (pyridin-2- yl)methanamineC₁₃H₁₀F₄N₂O (286.22) 64¹ A

(S)-(3-fluoro-4- (trifluoromethoxy) phenyl)(2- fluorophenyl) methanamineC₁₄H₁₀F₅NO (303.23) 65 C

(S)-(3,5- dimethylphenyl) (3- fluoropyridin- 2- yl)methanamine C₁₄H₁₅FN₂(230.28) 66 C

(S)-(3-fluoro-5- methylphenyl) (3- fluoropyridin- 2- yl)methanamineC₁₃H₁₂F₂N₂ (234.24) 67 C

(S)-(3-fluoro-5- (trifluoromethyl) phenyl)(3- fluoropyridin- 2-yl)methanamine C₁₃H₉F₅N₂ (288.22) 68 C

(S)-(3,5- difluorophenyl) (3- fluoropyridin- 2- yl)methanamine C₁₂H₉F₃N₂(238.21) 69 C

(S)-(3,4- difluorophenyl) (3- fluoropyridin- 2- yl)methanamine C₁₂H₉F₃N₂(238.21) 70 C

(S)-(3- fluoropyridin- 2-yl)(3-methyl- 5- (trifluoromethyl) phenyl)methanamine C₁₄H₁₂F₄N₂ (284.25) 71 A

(S)-(3-fluoro-4- methylphenyl) (3- fluoropyridin- 2- yl)methanamineC₁₃H₁₂F₂N₂ (234.24) 72 A

(S)-(3-fluoro-4- methoxyphenyl) (3-fluoropyridin- 2- yl)methanamineC₁₃H₁₂F₂N₂O (250.24) 73 B

(S)-(4-fluoro-3- methylphenyl) (3- fluoropyridin- 2- yl)methanamineC₁₃H₁₂F₂N₂ (234.24) 74 B

(S)-(4- fluorophenyl)(3- fluoropyridin- 2- yl)methanamine C₁₂H₁₀F₂N₂(220.22) 75 B

(S)-(3- fluoropyridin- 2-yl)(4- methoxyphenyl) methanamine C₁₃H₁₃FN₂O(232.25) 76 B

(S)-(4-chloro-3- fluorophenyl)(3- fluoropyridin- 2- yl)methanamineC₁₂H₉ClF₂N₂ (254.66) 77 A

(S)-(3-fluoro-4- (trifluoromethoxy) phenyl)(3- methylpyridin- 2-yl)methanamine C₁₄H₁₂F₄N₂O (300.25) 78 A

(S)-(3- methylpyridin- 2-yl)(4- (trifluoromethoxy) phenyl) methanamineC₁₄H₁₃F₃N₂O (282.26) 79 A

(S)-pyridin-2- yl(4- (trifluoromethoxy) phenyl) methanamine C₁₃H₁₁F₃N₂O(268.23) 80 A

(S)-(3- fluoropyridin- 2-yl)(p- tolyl) methanamine C₁₃H₁₃FN₂ (216.25) 81A

(S)-(3,4- dimethylphenyl) (3- fluoropyridin- 2- yl)methanamine C₁₄H₁₅FN₂(230.28) 82 A

(S)-3- fluoropyridin- 2-yl)(3-methyl- 4- (trifluoromethoxy) phenyl)methanamine C₁₄H₁₂F₄N₂O (300.25) 83 A

(S)-(3- bromopyridin- 2-yl)(3-fluoro- 4- (trifluoromethoxy) phenyl)methanamine C₁₃H₉BrF₄N₂O (365.12) 84 A

(S)-(2-fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin- 2-yl)methanamine C₁₃H₉F₅N₂O (304.22) 85 A

(S)-(3-fluoro-4- (trifluoromethyl) phenyl)(3- fluoropyridin- 2-yl)methanamine C₁₃H₉F₅N₂ (288.22) 86 A

(S)-(3-fluoro-4- (trifluoromethoxy) phenyl)(3- fluoro-6- methylpyridin-2- yl)methanamine C₁₄H₁₁F₅N₂O (318.24) 87² A

(3-fluoro-4- (trifluoromethoxy) phenyl)(4- fluorophenyl) methanamineC₁₄H₁₀F₅NO (303.23) 88² A

(2,3- difluorophenyl) (3-fluoro-4- (trifluoromethoxy) phenyl)methanamine C₁₄H₉F₆NO (321.22) 89² A

(2,4- difluorophenyl) (3-fluoro-4- (trifluoromethoxy) phenyl)methanamine C₁₄H₉F₆NO (321.22) 90² A

(2,5- difluorophenyl) (3-fluoro-4- (trifluoromethoxy) phenyl)methanamine C₁₄H₉F₆NO (321.22) 91² A

(3-fluoro-4- (trifluoromethoxy) phenyl)(3- fluorophenyl) methanamineC₁₄H₁₀F₅NO (303.23) 92² A

(2,6- difluorophenyl) (3-fluoro-4- (trifluoromethoxy) phenyl)methanamine C₁₄H₉F₆NO (321.22) 93² A

(3-fluoro-4- (trifluoromethoxy) phenyl)(6- methoxypyridin- 2-yl)methanamine C₁₄H₁₂F₄N₂O₂ (316.25) 94² A

(3-fluoro-4- (trifluoromethoxy) phenyl)(5- methoxypyridin- 2-yl)methanamine C₁₄H₁₂F₄N₂O₂ (316.25) 95² A

(3-fluoro-4- (trifluoromethoxy) phenyl)(4- methoxypyridin- 2-yl)methanamine C₁₄H₁₂F₄N₂O₂ (316.25) 96² A

(3-fluoro-4- (trifluoromethoxy) phenyl)(4- methylpyridin- 2-yl)methanamine C₁₄H₁₂F₄N₂O (300.25) 97² A

(3-fluoro-4- (trifluoromethoxy) phenyl)(5- methylpyridin- 2-yl)methanamine C₁₄H₁₂F₄N₂O (300.25) ¹Prepared employing(R)-2-methylpropane-2-sulfinamide in the first step (Scheme 5). Forreversal of stereochemistry observed in the Ellman sulfonylimincchemistry observed with 2-pyridyl substrates, see Kuduk, S.D.; DiPardo,R. M.; Chang, R. K.; Ng, C; Bock, M. G. Tetrahedron Lett. 2004, 45,6641-6643. ²Prepared employing racemic 2-methylpropane-2-sulfinamide inthe first step (Scheme 5)

Intermediate 98:(4-Iodophenyl)(3-(trifluoromethyl)pyridin-2-yl)methanamine Hydrochloride

Step 1. (E)-N-(4-Iodobenzylidene)-2-methylpropane-2-sulfinamide

To a solution of 4-(iodo)benzaldehyde (2.00 g, 8.62 mmol) (BioNetResearch) in DCM (20 mL) was added 2-methylpropane-2-sulfinamide (2.09g, 17.2 mmol) (AK Scientific) and copper (II) sulfate (2.75 g, 17.2mmol) (Fluka). The suspension was stirred at rt under N₂ for 17 h. Thesuspension was then filtered through Celite® brand filter agent, and thesolids were washed with DCM (2×20 mL). The filtrates were concentratedand purified by ISCO (80 g, SiO₂, 0-100% EtOAc/hexanes) to give thetitle compound as a yellow solid.

Step 2.N-((4-Iodophenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide

To a solution of 2-bromo-3-(trifluoromethyl)pyridine (750 mg, 3.32 mmol)(prepared as described in Schlosser, M. et al. Eur. J. Org. Chem. 2003,1559) in THF (5.0 mL) at −78° C. was added n-butyllithium (3.94 mL, 6.31mmol, 1.6 M in n-hexane). The resulting mixture was then stirred for 15min. N-(4-iodobenzylidene)-2-methylpropane-2-sulfinamide (556 mg, 1.66mmol) in THF (5 mL) was added, and the reaction was allowed to warm tort and stirred for 4 h. The reaction was quenched with saturated aqueousNH₄Cl (10 mL) and stirred rapidly for 1 h. The aqueous layer wasextracted with EtOAc (2×10 mL) and the combined organic layers weredried (MgSO₄) and concentrated. The product thus obtained was taken intothe next step without further purification.

Step 3. (4-Iodophenyl)(3-(trifluoromethyl)pyridin-2-yl)methanamine

To a solution ofN-((4-iodophenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamidein MeOH (5 mL) was added HCl (2.0 mL, 8.0 mmol) (4.0 M in 1,4-dioxane).The reaction was stirred at rt under N₂ for 18 h. The reaction was thenconcentrated, and the residue was purified by reverse-phase preparativeHPLC (Shimadzu) on a Phenomenex Gemini™ column (5 micron, C18, 110 Å,Axia, 100×30 mm) eluting at 45 mL/min with a linear gradient of 10% to100% MeCN (0.1% TFA) in H₂O (0.1% TFA) over 20 minutes. Theproduct-containing fractions were combined, concentrated, dissolved inDCM (5 mL) and extracted with saturated aqueous NaHCO₃ (2×5 mL). Theorganic layer was dried and concentrated to give(4-iodophenyl)(3-(trifluoromethyl)-pyridin-2-yl)methanamine as a clearoil.

Intermediate 99:(S)-(4-(Trifluoromethyl)phenyl)(3-vinylpyridin-2-yl)methanamine2,2,2-trifluoroacetate

Step 1. (S)-tert-Butyl((3-bromopyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamate

To a stirring solution of(S)—N—((S)-(3-bromopyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-2-methylpropane-2-sulfinamide(Intermediate 40, Step 4, 0.6 g, 1.38 mmol) in 1,4-dioxane (6 mL) at 0°C. was added HCl (4.0 M in dioxane solution, 12 mL, 27.6 mmol). Theresulting mixture was warmed to room temperature and stirred for 1 h.The reaction progress was monitored by TLC (20% EtOAc in petroleumether). After completion, Boc anhydride (0.76 g, 3.4 mmol) and DIPEA(0.28 g, 2 mmol) in 1,4-dioxane (5 mL) were added to the reactionmixture, and the mixture was stirred at room temperature for 1 h. Thereaction progress was monitored by TLC (20% EtOAc in petroleum ether).After completion of reaction, water (25 mL) was added to the reactionmixture, and the product was extracted with DCM (3×25 mL). The combinedorganic layers were dried over anhydrous sodium sulfate and purified bycolumn chromatography using silica (100-200 mesh) with 15-30% EtOAc inpetroleum ether as an eluent to afford the title compound as a whitesolid. MS (ESI pos. ion) m/z: 431.0 (M-100).

Step 2. (S)-tert-Butyl((4-(trifluoromethyl)phenyl)(3-vinylpyridin-2-yl)methyl)carbamate

To a mixture of (S)-tert-butyl((3-bromopyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)carbamate (0.4g, 0.93 mmol) in water (2 mL) and EtOH (8 mL) were added K₃PO₄ (0.3 g,1.3 mmol), vinyl boronic acid (4 mL, 9.3 mmol) and A^(−ta)Phos)₂PdCl₂(Guram, A. S. et al. Org. Lett. 2006, 8, 1787; 0.13 g, 0.01 mmol). Theresulting mixture was stirred at 120° C. for 1 h. Reaction progress wasmonitored by TLC (20% EtOAc in petroleum ether). After completion ofreaction, water (50 mL) was added to the reaction mixture, and theproduct was extracted with DCM (3×25 mL). The combined organic layerswere separated, dried over anhydrous sodium sulfate, and purified bycolumn chromatography using silica (100-200 mesh) and using 15-30% EtOAcin petroleum ether as an eluent. In this manner, (S)-tert-butyl((4-(trifluoromethyl)phenyl)(3-vinylpyridin-2-yl)methyl)carbamate wasobtained as an off-white solid. MS (ESI pos. ion) m/z: 378.9 (M+1).

Step 3. (S)-(4-(Trifluoromethyl)phenyl)(3-vinylpyridin-2-yl)methanamine2,2,2-trifluoroacetate

To a 50 mL round bottom flask containing (S)-tert-butyl((4-(trifluoromethyl)phenyl)(3-vinylpyridin-2-yl)methyl)carbamate (97mg, 0.256 mmol) was added DCM (3 mL). The resulting mixture was thenstirred at 23° C. for 2 min. At this time, TFA was added (3 mL) and thereaction was stirred for 3 h. The solvent was removed, and the materialwas immediately used with no further purification. MS (ESI pos. ion)m/z: 279.1 (M+1).

Intermediate 100:(R)-1-(2-Hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxylic Acid

Step 1. (R)-Methyl1-(2-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

A solution of methyl coumalate (500 mg, 3.24 mmol) in MeOH (10 mL) wastreated with (R)-(−)-1-amino-2-propanol (0.319 mL, 4.06 mmol) and TEA(0.790 mL, 5.68 mmol). The reaction was stirred at 23° C. undernitrogen. After 1 h, the reaction was concentrated and purified bysilica gel chromatography (eluent: 55-95% EtOAc/hexane), affording(R)-methyl 1-(2-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxylateas a white solid. MS (ESI pos. ion) m/z: 212.1 (M+1).

Step 2. (R)-1-(2-Hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxylicAcid

A solution of (R)-methyl1-(2-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (508 mg,2.405 mmol) in 1,4-dioxane (12 mL) and MeOH (4.00 mL) was treated withaqueous sodium hydroxide, 5.0 M (0.962 mL, 4.81 mmol). The reaction wasstirred at 23° C. After 20 h, the reaction was neutralized to pH=6.0with 2 N HCl, and concentrated in vacuo. The residue was azeotroped withtoluene (3×10 mL), suspended in a 1:1 MeOH:DCM solution (25 mL), and thewhite NaCl residue was removed by filtration. The filtrate wasconcentrated, affording(R)-1-(2-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid as awhite solid. MS (ESI pos. ion) m/z: 198.1 (M+1).

TABLE 4 Additional carboxylic acids prepared from methyl coumalateanalogous to Scheme 16 (Intermediate 101-110) Mol. Amine FormulaIntermediate in Step 1 Structure Name (Mol. Wt.) 101

1-(2- hydroxyethyl)- 6-oxo-1,6- dihydropyridine- 3-carboxylic acidC₈H₉NO₄ (183.16) 102

(S)-1-(2- hydroxypropyl)- 6-oxo-1,6- dihydropyridine- 3-carboxylic acidC₉H₁₁NO₄ (197.19) 103

1-(2-hydroxy- 2- methylpropyl)- 6-oxo-1,6- dihydropyridine- 3-carboxylicacid C₁₀H₁₃NO₄ (211.21) 104

1-(oxetan-3-yl)- 6-oxo-1,6- dihydropyridine- 3-carboxylic acid C₉H₉NO₄(195.17) 105

1-ethyl-6-oxo- 1,6- dihydropyridine- 3-carboxylic acid C₈H₉NO₃ (167.16)106

1-isopropyl-6- oxo-1,6- dihydropyridine- 3-carboxylic acid C₉H₁₁NO₃(181.19) 107

6-oxo-1-(2,2,2- trifluoroethyl)- 1,6- dihydropyridine- 3-carboxylic acidC₈H₆F₃NO₃ (221.13) 108

1-((1- hydroxy- cyclopropyl) methyl)-6- oxo-1,6- dihydropyridine-3-carboxylic acid C₁₀H₁₁NO₄ (209.20) 109

(S)-6-oxo-1- (3,3,3-trifluoro- 2- hydroxypropyl)- 1,6- dihydropyridine-3-carboxylic acid C₉H₈F₃NO₄ (251.16) 110

(R)-6-oxo-1- (3,3,3-trifluoro- 2- hydroxypropyl)- 1,6- dihydropyridine-3-carboxylic acid C₉H₈F₃NO₄ (251.16)

Intermediate 111: 1-Methoxy-6-oxo-1,6-dihydropyridine-3-carboxylic Acid

Step 1. 2-Chloro-5-(methoxycarbonyl)pyridine 1-oxide

To a 500 mL round bottom flask containing methyl 6-chloronicotinate(4.50 g, 26.2 mmol) was added MeCN (100 mL). The resulting mixture wasthen stirred at 0° C. for 10 min. At this time, urea hydrogen peroxide(4.93 g, 52.5 mmol) solid was added before the dropwise addition oftrifluoroacetic anhydride (7.41 mL, 52.5 mmol). The reaction was stirredfor 30 min and then the ice bath was removed. The reaction was thenstirred for 3 h and then the bulk of MeCN was removed by rotaryevaporation. The residue was dissolved in EtOAc (150 mL) and washed withsodium thiosulfate (aqueous, 0.5 M, 2×100 mL), water (100 mL), brine(100 mL), dried with sodium sulfate and concentrated to a tan solid. Thesolid thus obtained was dissolved in DCM (150 mL) and MeOH (30 mL). Thesolid residue was removed by filtration, and the filtrate wasconcentrated affording 2-chloro-5-(methoxycarbonyl)pyridine 1-oxide as atan solid.

Step 2. Methyl 1-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate

To a 250 mL round bottom flask containing2-chloro-5-(methoxycarbonyl)pyridine 1-oxide (2.45 g, 13.06 mmol) wasadded MeCN (10 mL). The resulting mixture was stirred at 23° C. for 5min. At this time, trifluoroacetic anhydride (20 mL) was added and thereaction was stirred 1 h. Solid NaHCO₃ (25 g) was added to the flaskfollowed by MeOH (100 mL). The solid was filtered away and the filtratewas concentrated and subjected to silica gel chromatography (80 g ISCOcolumn, 0-5% MeOH in CHCl₃) to give methyl1-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate as a yellow solid.

Step 3. Methyl 1-methoxy-6-oxo-1,6-dihydropyridine-3-carboxylate

To a solution of methyl1-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate (0.75 g, 4.43 mmol) in5 mL DMF at 23° C., were added potassium carbonate (1.8 g, 13.3 mmol)and MeI (1.5 g, 11 mmol). The resulting mixture was stirred overnightand then MeOH (6 mL) was added and the resulting mixture was stirred for2 h. The volatiles were removed under vacuum, and the resulting residuewas dissolved in EtOAc (75 mL), washed with water (2×50 mL), brine (50mL), dried (MgSO₄), and concentrated to give methyl1-methoxy-6-oxo-1,6-dihydropyridine-3-carboxylate as a brown oil.

Step 4. 1-Methoxy-6-oxo-1,6-dihydropyridine-3-carboxylic Acid

A solution of methyl 1-methoxy-6-oxo-1,6-dihydropyridine-3-carboxylate(64 mg, 0.349 mmol) and potassium trimethylsilanolate (90 mg, 0.699mmol) in THF (6 mL) was stirred at 23° C. for 20 min. MeOH (5 mL) wasadded, and the mixture was filtered. The filtrate was concentratedaffording 1-methoxy-6-oxo-1,6-dihydropyridine-3-carboxylic acid as awhite solid.

Intermediate 112:1-(Difluoromethyl)-6-oxo-1,6-dihydropyridine-3-carboxylic Acid

Step 1. Methy 6-acetamidonicotinate

To a mixture of methyl 6-aminopyridine-3-carboxylate (3 g, 19.72 mmol,Aldrich) in 1,4-ioxane (50 mL) was added acetic anhydride (3.72 mL, 39.4mmol, Aldrich). The resulting mixture was then heated at 85° C. for 3 hand at 100° C. for an additional 3 h. The mixture was then cooled to rtand diluted with EtOAc (400 mL). The mixture was then washed withsaturated NaHCO₃ solution (2×200 mL), brine (150 mL), dried over MgSO₄,and concentrated in vacuo to afford the title compound as a white solid,which was used in the next step without purification. MS (ESI, positiveion) m/z: 195 (M+H).

Step 2. Methyl1-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

A mixture of methyl 6-acetamidonicotinate (1.93 g, 9.94 mmol), sodiumchlorodifluoroacetate (1.818 g, 11.93 mmol, Alfa Aesar AvocadoLancaster) and 18-crown-6 (0.525 g, 1.988 mmol, Aldrich) in MeCN (40 mL)was heated to 90° C. (reflux) under nitrogen. After 5 h, a solution ofKHSO₄ (1% in H₂O, 10 mL) was added and the mixture was refluxed for 21h. The mixture was then cooled to room temperature and concentrated. Themixture was diluted with EtOAc (250 mL), washed with 10% aqueoushydrochloric acid (100 mL), and then with saturated aqueous NaHCO₃ (100mL), and finally with brine (100 mL). The mixture was dried (MgSO₄) andconcentrated in vacuo. The residue was dissolved in DCM (5 mL), and thesolution was purified by silica gel flash column chromatography (5-30%EtOAc/hexane) to afford the title compound as a white solid. MS (ESI,positive ion) m/z: 204 (M+H).

Step 3. 1-(Difluoromethyl)-6-oxo-1,6-dihydropyridine-3-carboxylic Acid

To a solution of methyl1-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (0.500 g,2.461 mmol) in MeOH (12 mL) and water (4 mL) was added lithium hydroxidehydrate (0.207 g, 4.92 mmol, Aldrich). The resulting mixture was thenstirred at room temperature for 4 h. Solvent (MeOH) was removed invacuok, and the remaining aqueous solution was adjusted to pH=5-6 byaddition of concentrated HCl. The mixture was then extracted with EtOAc(3×10 mL). The combined organic layers were dried (MgSO₄), and thesolvent removed to give the title compound as a yellow solid. MS (ESI,positive ion) m/z: 190 (M+H).

Intermediate 113: 5-Fluoro-6-oxo-1,6-dihydropyridine-3-carboxylic Acid

Step 1. Methyl 5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylate

To a solution of methyl 6-oxo-1,6-dihydro-3-pyridinecarboxylate (2.00 g,13.06 mmol, Bionet Research) in MeCN (40 mL) was added SelectFluor®(4.63 g, 13.06 mmol, Aldrich). The resulting mixture was then heated at65° C. for 18 h. Then, the mixture was cooled to rt and water (20 mL)was added. The solvent, (MeCN) was removed and the remaining aqueoussolution was extracted with EtOAc (2×20 mL). The combined organicextracts were dried (MgSO₄) and concentrated in vacuo. The residue wasdissolved in MeOH (100 mL) and silica gel was added. The mixture wasconcentrated and dried in vacuo. Purification by silica gel flash columnchromatography (0%-100% EtOAc/hexane) gave the title compound as a whitesolid. MS (ESI, positive ion) m/z: 172 (M+H).

Step 2. 5-Fluoro-6-oxo-1,6-dihydropyridine-3-carboxylic Acid

To a solution of methyl 5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylate(0.876 g, 5.12 mmol) in MeOH (33 mL) and water (11 mL), was addedlithium hydroxide hydrate (1.074 g, 25.6 mmol). The resulting mixturewas then stirred at rt for 5 h. The mixture was concentrated and the pHwas adjusted to pH=5 using concentrated HCl. The mixture was thenconcentrated and dried in vacuo. The resulting residue was dissolved inMeOH (20 mL) and silica gel was added. The mixture was concentrated anddried. The solid mixture was then purified by silica gel flash columnchromatography (30%-100% EtOAc/hexane, then 0%-100% MeOH/DCM) to givethe title compound as an off-white solid. MS (ESI, positive ion) m/z:158 (M+H).

Intermediate 114: 5-Chloro-6-oxo-1,6-dihydropyridine-3-carboxylic Acid

To a solution of 6-hydroxy nicotinic acid (0.500 g, 3.59 mmol, TCI) inMeCN (20 mL), was added N-chlorosuccinimide (0.436 mL, 5.39 mmol,Aldrich). The resulting mixture was then heated at 80° C. for 72 h. Awhite precipitate was present. The mixture was filtered and the whitesolid was washed with EtOAc (2×1 mL) and dried in vacuo to afford thetitle compound as a white solid. MS (ESI, positive ion) m/z: 174, 176(M+H).

Intermediate 115:6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carboxylic Acid

To a solution of 5-bromo-3-(trifluoromethyl)pyridin-2-ol (0.960 g, 3.97mmol, Aldrich) in THF (20 mL) at −78° C. under N₂ was slowly addedn-butyllithium solution, 1.6 M in hexane (5.45 mL, 8.73 mmol). Afteraddition, the mixture was stirred at −78° C. for 30 min. Then, dry icewas added and the mixture was stirred at −78° C. for 30 min and at rtfor 30 min. Water (20 mL) was then added slowly, and the mixture wasstirred at rt for 15 min. The aqueous phase was collected and acidified(pH=5-6) using concentrated HCl. The mixture was extracted with EtOAc(3×15 mL). The combined organic layers were dried (MgSO₄), concentrated,and dried in vacuo to give the title compound as a yellow solid. MS(ESI, positive ion) m/z: 208 (M+H).

Intermediate 116: 5-Methyl-6-oxo-1,6-dihydropyridine-3-carboxylic Acid

Step 1. 5-Bromo-3-methylpyridin-2(1H)-one

To a solution of 2-hydroxy-3-methylpyridine (0.500 g, 4.58 mmol, AcrosOrganics) in DCM (15 mL) was slowly added bromine (0.282 mL, 5.50 mmol).After addition, the mixture was stirred at rt for 18 h. The mixture wascooled to 0° C. and was quenched with saturated aqueous NaHCO₃ (5 mL).The mixture was then extracted with EtOAc (3×20 mL). The combinedorganic layer were dried over MgSO₄ and concentrated. The residue wasthen dissolved in MeOH (20 mL) and silica gel was added. The mixture wasconcentrated and dried in vacuo. The resulting mixture was then purifiedby silica gel flash column chromatography (solid loading, 0%-100%EtOAc/hexane) to afford the title compound as a light pink solid. MS(ESI, positive ion) m/z: 188, 190 (M+H).

Step 2. 5-Methyl-6-oxo-1,6-dihydropyridine-3-carboxylic Acid

To a solution of 5-bromo-3-methylpyridin-2(1H)-one (0.400 g, 2.127 mmol)in THF (9 mL) at −78° C. under N₂ was slowly added n-butyllithiumsolution, 1.6 M in hexane (5.32 mL, 8.51 mmol). After addition, themixture was stirred at −78° C. for 20 min. The mixture was then quenchedwith dry ice and allowed to warm to 0° C. and stirred for 60 min. Themixture was then immersed in a 0° C. bath and the pH was adjusted topH=5-6 using concentrated HCl. The mixture was concentrated and dried invacuo to give the title compound as a light brown solid. MS (ESI,positive ion) m/z: 154 (M+H).

Intermediate 117: 5-Methoxy-6-oxo-1,6-dihydropyridine-2-carboxylic Acid

Step 1. 6-Bromo-3-methoxypyridin-2(1H)-one

To a solution of 3-methoxy-2(1 h)-pyridone (1.00 g, 7.99 mmol, AstaTech,Inc) in DCM (26 mL) at 0° C. was slowly added bromine (0.819 mL, 15.98mmol). After addition, the mixture was stirred at rt for 18 h. Themixture was then cooled to 0° C. and saturated aqueous NaHCO₃ (4 mL) wasslowly added. The mixture was then stirred at rt for 30 min. The organiclayer was collected and the aqueous layer was extracted with EtOAc (1×20mL). The combined organic layers were dried over MgSO₄ and concentratedin vacuo. The residue was then dissolved in MeOH (20 mL) and silica gelwas added. The mixture was concentrated and dried in vacuo. The solidmixture was purified by silica gel flash column chromatography (solidloading, 0%-100% EtOAc/hexane) to give the title compound as a tansolid. MS (ESI, positive ion) m/z: 204, 206 (M+H).

Step 2. 5-Methoxy-6-oxo-1,6-dihydropyridine-2-carboxylic Acid

To a solution of 6-bromo-3-methoxypyridin-2(1H)-one (0.200 g, 0.980mmol) in THF (3.5 mL) under N₂ at −78° C. was added n-butyllithiumsolution, 1.6 M in hexanes (2.5 mL, 3.9 mmol) slowly. After addition,the mixture was stirred at −78° C. for 20 min. Then, the mixture wasquenched with dry ice at −78° C. The mixture was then stirred at 0° C.for 1 h. The resulting mixture was adjusted to pH=5-6 using concentratedHCl. The mixture was stirred at rt for 15 min. Then, the aqueous layerwas collected, concentrated, and dried in vacuo. Then, a solution ofDCM/MeOH (1:1, 20 mL) was added to the residue, and the mixture wasstirred at rt for 10 min. The mixture was filtered and filtrate wascollected, dried over MgSO₄, concentrated, and dried in vacuo to affordthe title compound as a light brown solid. MS (ESI, positive ion) m/z:170 (M+H).

TABLE 5 Examples 287-424 prepared via amide formation analogous toScheme 4 Product Product MS Ex # Amine Acid Structure Structure Name M +H 287¹ 2b

(R)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)-6-oxo-1,6- dihydropyridine- 3-carboxamide 392.1 288 6

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-yl)methyl)-2- (pyridin-2- yl)acetamide 424.1 289 6

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-yl)methyl)-2- (pyridin-3- yl)acetamide 424.1 290 6

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-yl)methyl)-2- (pyridin-4- yl)acetamide 424.0 291 61

(S)-N-((3,6- difluoropyridin- 2-yl)(4- (trifluoromethyl) phenyl)methyl)-6-oxo-1,6- dihydropyridine- 3-carboxamide 410.1 292 62

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(5- fluoropyridin-2-yl)methyl)-6- oxo-1,6- dihydropyridine- 3-carboxamide 426.0 293 63

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl) (pyridin-2-yl)methyl)-6- oxo-1,6- dihydropyridine- 3-carboxamide 408.0 294 63

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(pyridin- 2-yl)methyl)-1-methyl-6-oxo- 1,6- dihydropyridine- 3-carboxamide 422.1 295 64

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(2- fluorophenyl)methyl)-6-oxo- 1,6- dihydropyridine- 3-carboxamide 425.1 296 64

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(2- fluorophenyl)methyl)-1- methyl-6-oxo- 1,6- dihydropyridine- 3-carboxamide 439.1 297 6101

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-yl)methyl)-1-(2- hydroxyethyl)- 6-oxo-1,6- dihydropyridine-3-carboxamide 470.1 298 6 102

N-((S)-(3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-yl)methyl)-1- ((S)-2- hydroxypropyl)- 6-oxo-1,6- dihydropyridine-3-carboxamide 484.1 299 6 100

N-((S)-(3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-yl)methyl)-1- ((R)-2- hydroxypropyl)- 6-oxo-1,6- dihydropyridine-3-carboxamide 484.1 300 2 102

N-((S)-(3- fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)-1-((S)-2- hydroxypropyl)- 6-oxo-1,6- dihydropyridine- 3-carboxamide450.1 301 2 100

N-((S)-(3- fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)-1-((R)-2- hydroxypropyl)- 6-oxo-1,6- dihydropyridine- 3-carboxamide450.1 302 6 103

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-yl)methyl)-1-(2- hydroxy-2- methylpropyl)- 6-oxo-1,6- dihydropyridine-3-carboxamide 498.2 303 2 103

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)-1-(2-hydroxy- 2- methylpropyl)- 6-oxo-1,6- dihydropyridine-3-carboxamide 464.1 304 6 104

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-yl)methyl)-1- (oxetan-3-yl)-6- oxo-1,6- dihydropyridine- 3-carboxamide482.1 305 2 104

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)-1-(oxetan-3- yl)-6-oxo-1,6- dihydropyridine- 3-carboxamide 448.1 306 28

(S)-N- (phenyl(3- (trifluoromethyl) pyridin-2- yl)methyl) quinoline-7-carboxamide 408.0 307 2

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)tetrazolo[1,5- a]pyridine-6- carboxamide 417.2 308 2

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)tetrazolo[1,5- a]pyridine-7- carboxamide 417.2 309 8

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethoxy) phenyl)methyl)tetrazolo[1,5- a]pyridine-6- carboxamide 433.1 310 8

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethoxy) phenyl)methyl)tetrazolo[1,5- a]pyridine-7- carboxamide 433.1 311 1

(S)-N-((4- (trifluoromethyl) phenyl)(3- (trifluoromethyl) pyridin-2-yl)methyl) tetrazolo[1,5- a]pyridine-6- carboxamide 467.1 312 1

(S)-N-((4- (trifluoromethyl) phenyl)(3- (trifluoromethyl) pyridin-2-yl)methyl) tetrazolo[1,5- a]pyridine-7- carboxamide 467.1 313 44

(S)-N-((3- methylpyridin- 2-yl)(4- (trifluoromethyl) phenyl)methyl)-2-oxo-2,3- dihydrobenzo[d] oxazole-6- carboxamide 428.1 314 44

(S)-N-((3- methylpyridin- 2-yl)(4- (trifluoromethyl) phenyl)methyl)imidazo[1,2- a]pyridine-6- carboxamide 411.2 315 2

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)-4-(5-oxo-2,5- dihydro-1,2,4- oxadiazol-3- yl)benzamide 459.0 316 8

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethoxy) phenyl)methyl)-4-(5-oxo- 2,5-dihydro- 1,2,4-oxadiazol- 3-yl)benzamide 475.1 317 2

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)-6-oxo-1,6- dihydropyridazine- 3-carboxamide 393.2 318 2

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)-2-oxo-1,2,3,4- tetrahydroquinoline- 6-carboxamide 444.2 319 2

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)-5-oxo-4,5- dihydropyrazine- 2-carboxamide 393.2 320 2

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)-6,7-dihydro- 5H- pyrazolo[5,1- b][1,3]oxazine- 2-carboxamide 421.1 321 2

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)-1,4,5,6- tetrahydrocyclo penta[c]pyrazole- 3- carboxamide 405.2 322 2

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)-4,5,6,7- tetrahydro-1H- indazole-3- carboxamide 419.1 323 44

(S)-N-((3- methylpyridin- 2-yl)(4- (trifluoromethyl) phenyl)methyl)-4-(5-oxo-2,5- dihydro-1,2,4- oxadiazol-3- yl)benzamide 455.1 324 65

(S)-N-((3,5- dimethylphenyl) (3- fluoropyridin-2- yl)methyl)-6- oxo-1,6-dihydropyridine- 3-carboxamide 352.1 325 66

(S)-N-((3- fluoro-5- methylphenyl) (3-fluoropyridin- 2-yl)methyl)-6-oxo-1,6- dihydropyridine- 3-carboxamide 356.1 326 66

(S)-N-((3- fluoro-5- methylphenyl) (3-fluoropyridin- 2-yl)methyl)-1-methyl-6-oxo- 1,6- dihydropyridine- 3-carboxamide 370.1 327 67

(S)-N-((3- fluoro-5- (trifluoromethyl) phenyl)(3- fluoropyridin-2-yl)methyl)-6- oxo-1,6- dihydropyridine- 3-carboxamide 410.1 328 67

(S)-N-((3- fluoro-5- (trifluoromethyl) phenyl)(3- fluoropyridin-2-yl)methyl)-1- methyl-6-oxo- 1,6- dihydropyridine- 3-carboxamide 424.1329 68

(S)-N-((3,5- difluorophenyl) (3-fluoropyridin-2- yl)methyl)-6- oxo-1,6-dihydropyridine- 3-carboxamide 360.0 330 68

(S)-N-((3,5- difluorophenyl) (3- fluoropyridin-2- yl)methyl)-1-methyl-6-oxo- 1,6- dihydropyridine- 3-carboxamide 374.1 331 69

(S)-N-((3,4- difluorophenyl) (3- fluoropyridin-2- yl)methyl)-6- oxo-1,6-dihydropyridine- 3-carboxamide 360.0 332 69

(S)-N-((3,4- difluorophenyl) (3-fluoropyridin-2- yl)methyl)-1-methyl-6-oxo- 1,6- dihydropyridine- 3-carboxamide 374.0 333 70

(S)-N-((3- fluoropyridin-2- yl)(3-methyl-5- (trifluoromethyl)phenyl)methyl)- 6-oxo-l,6- dihydropyridine- 3-carboxamide 406.1 334 71

(S)-N-((3- fluoro-4- methylphenyl) (3-fluoropyridin- 2-yl)methyl)-6-oxo-1,6- dihydropyridine- 3-carboxamide 356.0 335 71

(S)-N-((3- fluoro-4- methylphenyl) (3-fluoropyridin- 2-yl)methyl)-1-methyl-6-oxo- 1,6- dihydropyridine- 3-carboxamide 370.1 336 72

(S)-N-((3- fluoro-4- methoxyphenyl) (3- fluoropyridin-2- yl)methyl)-6-oxo-1,6- dihydropyridine- 3-carboxamide 372.0 337 72

(S)-N-((3- fluoro-4- methoxyphenyl) (3- fluoropyridin-2- yl)methyl)-1-methyl-6-oxo- 1,6- dihydropyridine- 3-carboxamide 386.0 338 73

(S)-N-((4- fluoro-3- methylphenyl) (3-fluoropyridin- 2-yl)methyl)-6-oxo-1,6- dihydropyridine- 3-carboxamide 356.0 339 73

(S)-N-((4- fluoro-3- methylphenyl) (3-fluoropyridin- 2-yl)methyl)-1-methyl-6-oxo- 1,6- dihydropyridine- 3-carboxamide 370.1 340 74

(S)-N-((4- fluorophenyl)(3- fluoropyridin- 2-yl)methyl)-6- oxo-1,6-dihydropyridine- 3-carboxamide 342.0 341 74

(S)-N-((4- fluorophenyl)(3- fluoropyridin- 2-yl)methyl)-1- methyl-6-oxo-1,6- dihydropyridine- 3-carboxamide 356.0 342 75

(S)-N-((3- fluoropyridin-2- yl)(4- methoxyphenyl) methyl)-6-oxo- 1,6-dihydropyridine- 3-carboxamide 354.0 343 75

(S)-N-((3- fluoropyridin-2- yl)(4- methoxyphenyl) methyl)-1-methyl-6-oxo- 1,6- dihydropyridine- 3-carboxamide 368.0 344 76

(S)-N-((4- chloro-3- fluorophenyl)(3- fluoropyridin- 2-yl)methyl)-6-oxo-1,6- dihydropyridine- 3-carboxamide 376.0 345 76

(S)-N-((4- chloro-3- fluorophenyl)(3- fluoropyridin- 2-yl)methyl)-1-methyl-6-oxo- 1,6- dihydropyridine- 3-carboxamide 390.0 346 6

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-yl)methyl)-2- oxoindoline-5- carboxamide 464.0 347 77

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- methylpyridin-2-yl)methyl)-6- oxo-1,6- dihydropyridine- 3-carboxamide 422.0 348 77

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- methylpyridin-2-yl)methyl)-1- methyl-6-oxo- 1,6- dihydropyridine- 3-carboxamide 436.0349 6

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-yl)methyl)-6- oxo-1,6- dihydropyridazine- 3-carboxamide 427.0 350 8

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethoxy) phenyl)methyl)-6-oxo-1,6- dihydropyridazine- 3-carboxamide 409.0 351 6

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-yl)methyl)-2- oxo-1,2,3,4- tetrahydroquinoline- 6-carboxamide 478.0 3528

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethoxy) phenyl)methyl)-2-oxo- 1,2,3,4- tetrahydroquinoline- 6-carboxamide 460.0 353 6

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-yl)methyl)-5- oxo-4,5- dihydropyrazine- 2-carboxamide 427.0 354 8

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethoxy) phenyl)methyl)-5-oxo-4,5- dihydropyrazine- 2-carboxamide 409.0 355 6

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-yl)methyl)-6,7- dihydro-5H- pyrazolo[5,1- b][1,3]oxazine- 2-carboxamide455.0 356 8

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethoxy) phenyl)methyl)-6,7-dihydro- 5H-pyrazolo[5,1- b][1,3]oxazine- 2-carboxamide 437.0 357 77

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- methylpyridin-2-yl)methyl)-3- oxo-3,4- dihydro-2H- benzo[b][1,4] oxazine-7-carboxamide 476.0 358 77

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- methylpyridin-2-yl)methyl)-2- oxo-2,3- dihydrobenzo[d] oxazole-5- carboxamide 462.0359 78

(S)-N-((3- methylpyridin- 2-yl)(4- (trifluoromethoxy) phenyl)methyl)-6-oxo-1,6- dihydropyridine- 3-carboxamide 404.0 360 78

(S)-1-methyl-N- ((3- methylpyridin- 2-yl)(4- (trifluoromethoxy)phenyl)methyl)- 6-oxo-1,6- dihydropyridine- 3-carboxamide 418.1 361 54

(S)-2-oxo-N- (pyridin-2-yl(4- (trifluoromethyl) phenyl)methyl)- 2,3-dihydrobenzo[d] oxazole-5- carboxamide 414.0 362 79

(S)-2-oxo-N- (pyridin-2-yl(4- (trifluoromethoxy) phenyl) methyl)-2,3-dihydrobenzo[d] oxazole-5- carboxamide 430.0 363 99

(S)-6-oxo-N- ((4- (trifluoromethyl) phenyl)(3- vinylpyridin-2-yl)methyl)-1,6- dihydropyridine- 3-carboxamide 400.1 364 2 105

(S)-1-ethyl-N- ((3- fluoropyridin-2- yl)(4- (trifluoromethyl)phenyl)methyl)- 6-oxo-1,6- dihydropyridine- 3-carboxamide 420.2 365 36105

(S)-N-((3,4- dichlorophenyl) (3- fluoropyridin-2- yl)methyl)-1-ethyl-6-oxo-1,6- dihydropyridine- 3-carboxamide 420.1 366 6 105

(S)-1-ethyl-N- ((3-fluoro-4- (trifluoromethoxy) phenyl)(3-fluoropyridin-2- yl)methyl)-6- oxo-1,6- dihydropyridine- 3-carboxamide454.1 367 2 106

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)-1-isopropyl-6- oxo-1,6- dihydropyridine- 3-carboxamide 434.1 368 2

(S)-5-bromo-N- ((3- fluoropyridin-2- yl)(4- (trifluoromethyl)phenyl)methyl)- 6-oxo-1,6- dihydropyridine- 3-carboxamide 470 369 2 111

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)-1-methoxy-6- oxo-1,6- dihydropyridine- 3-carboxamide 422.1 370 2 101

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)-1-(2- hydroxyethyl)- 6-oxo-1,6- dihydropyridine- 3-carboxamide 436.2 3712

(S)-1-benzyl-N- ((3- fluoropyridin-2- yl)(4- (trifluoromethyl)phenyl)methyl)- 6-oxo-1,6- dihydropyridine- 3-carboxamide 482.2 372 2107

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)-6-oxo-1-(2,2,2- trifluoroethyl)- 1,6- dihydropyridine- 3-carboxamide474.1 373 2 116

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)-5-methyl-6- oxo-1,6- dihydropyridine- 3-carboxamide 406.1 374 8

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethoxy) phenyl)methyl)thiophene-2- carboxamide 397.1 375 2

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)thiophene-2- carboxamide 381.1 376 98

N-((4- iodophenyl)(3- (trifluoromethyl) pyridin-2- yl)methyl)-6-oxo-1,6- dihydropyridine- 3-carboxamide 499.5 377 79

(S)-6-oxo-N- (pyridin-2-yl(4- (trifluoromethoxy) phenyl)methyl)-1,6-dihydropyridine- 3-carboxamide 389.7 378 79

(S)-1-methyl-6- oxo-N-(pyridin- 2-yl(4- (trifluoromethoxy) phenyl)methyl)-1,6- dihydropyridine- 3-carboxamide 403.9 379 80

(S)-N-((3- fluoropyridin-2- yl)(p- tolyl)methyl)-6- oxo-1,6-dihydropyridine- 3-carboxamide 337.9 380 81

(S)-N-((3,4- dimethylphenyl) (3-fluoropyridin-2- yl)methyl)-6- oxo-1,6-dihydropyridine- 3-carboxamide 351.8 381 82

(S)-N-((3- fluoropyridin-2- yl)(3-methyl-4- (trifluoromethoxy)phenyl)methyl)- 6-oxo-1,6- dihydropyridine- 3-carboxamide 421.9 382 83

(S)-N-((3- bromopyridin- 2-yl)(3-fluoro- 4- (trifluoromethoxy)phenyl)methyl)- 6-oxo-1,6- dihydropyridine- 3-carboxamide 486.0 488.0383 26

(S)-N-((3- fluoro-4- (tritluoromethoxy) phenyl)(3- (trifluoromethyl)pyridin-2- yl)methyl)-6- oxo-1,6- dihydropyridine- 3-carboxamide 476.0384 83

(S)-N-((3- bromopyridin- 2-yl)(3-fluoro- 4- (trifluoromethoxy)phenyl)methyl)- 2-oxo-2,3- dihydrobenzo[d] oxazole-5- carboxamide 526.0528.0 385 26

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- (trifluoromethyl)pyridin-2- yl)methyl)-2- oxo-2,3- dihydrobenzo[d] oxazole-5- carboxamide516.0 386 84

(S)-N-((2- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-yl)methyl)-6- oxo-1,6- dihydropyridine- 3-carboxamide 2,2,2-trifluoroacetate 426.0 387 6

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-yl)methyl)-1- methyl-1H- imidazole-2- carboxamide 2,2,2-trifluoroacetate 413.0 388 6

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-yl)methyl)-4- methyl-1H- imidazole-2- carboxamide 2,2,2-trifluoroacetate 413.0 389 6

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-yl)methyl)-5- hydroxypicolinamide 2,2,2- trifluoroacetate 426.0 390 6

(S)-4- acetamido-N- ((3-fluoro-4- (trifluoromethoxy) phenyl)(3-fluoropyridin-2- yl)methyl)-3- hydroxybenzamide 482.0 391 63

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(pyridin-2- yl)methyl)-2-oxo-2,3- dihydrobenzo[d] oxazole-6- carboxamide 448.0 392 2

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)-1H-benzo[d]imidazole- 5-carboxamide 415.1 393 63

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(pyridin-2-yl)methyl)-1H- benzo[d]imidazole- 5-carboxamide 431.0 394 2

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)-1-methyl-1H- benzo[d]imidazole- 5-carboxamide 429.0 395 2

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)-1-methyl-1H- benzo[d]imidazole- 6-carboxamide 429.0 396 2 112

(S)-1- (difluoromethyl)- N-((3- fluoropyridin-2- yl)(4-(trifluoromethyl) phenyl)methyl)- 6-oxo-1,6- dihydropyridine-3-carboxamide 442.0 397 2

(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)-2-methyl-1H- benzo[d] imidazole-5- carboxamide 429.2 398 6

(S)-methyl 6- (((3-fluoro-4- (trifluoromethoxy) phenyl)(3-fluoropyridin-2- yl)methyl) carbamoyl)nicotinate 468.0 399 6 112

(S)-1- (difluoromethyl)- N-((3-fluoro-4- (trifluoromethoxy) phenyl)(3-fluoropyridin-2- yl)methyl)-6- oxo-1,6- dihydropyridine- 3-carboxamide476.0 400 6 113

(S)-5-fluoro-N- ((3-fluoro-4- (trifluoromethoxy) phenyl)(3-fluoropyridin-2- yl)methyl)-6- oxo-1,6- dihydropyridine- 3-carboxamide444.0 401 6 114

(S)-5-chloro-N- ((3-fluoro-4- (trifluoromethoxy) phenyl)(3-fluoropyridin-2- yl)methyl)-6- oxo-1,6- dihydropyridine- 3-carboxamide460.0 462.0 402 6 115

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-yl)methyl)-6- oxo-5- (trifluoromethyl)- 1,6- dihydropyridine-3-carboxamide 494.0 403 6 116

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-yl)methyl)-5- methyl-6-oxo- 1,6- dihydropyridine- 3-carboxamide 440.1404 6 117

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-yl)methyl)-5- methoxy-6-oxo- 1,6- dihydropyridine- 2-carboxamide 456.0405 85

(S)-N-((3- fluoro-4- (trifluoromethyl) phenyl)(3- fluoropyridin-2-yl)methyl)-6- oxo-1,6- dihydropyridine- 3-carboxamide 410.0 406 63

(S)-methyl 6- (((3-fluoro-4- (trifluoromethoxy) phenyl)(pyridin-2-yl)methyl) carbamoyl)nicotinate 450.0 407 6 108

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-yl)methyl)-1- ((1-hydroxy- cyclopropyl) methyl)-6- oxo-1,6-dihydropyridine- 3-carboxamide 496.1 408 6 109

N-((S)-(3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-yl)methyl)-6- oxo-1-((S)- 3,3,3-trifluoro- 2-hydroxypropyl)- 1,6-dihydropyridine- 3-carboxamide 538.1 409 6 110

N-((S)-(3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-yl)methyl)-6- oxo-1-((R)- 3,3,3-trifluoro- 2-hydroxypropyl)- 1,6-dihydropyridine- 3-carboxamide 538.1 410 86

(S)-N-((3- fluoro-6- methylpyridin- 2-yl)(4- (trifluoromethyl)phenyl)methyl)- 6-oxo-1,6- dihydropyridine- 3-carboxamide 406.1 411 87

N-((3-fluoro-4- (trifluoromethoxy) phenyl)(4- fluorophenyl)methyl)-6-oxo- 1,6- dihydropyridine- 3-carboxamide 425.0 412 88

N-((2,3- difluorophenyl) (3-fluoro-4- (trifluoromethoxy) phenyl)methyl)-6-oxo-1,6- dihydropyridine- 3-carboxamide 442.8 413 89

N-((2,4- difluorophenyl) (3-fluoro-4- (trifluoromethoxy) phenyl)methyl)-6-oxo-l,6- dihydropyridine- 3-carboxamide 442.8 414 90

N-((2,5- difluorophenyl) (3-fluoro-4- (trifluoromethoxy) phenyl)methyl)-6-oxo-1,6- dihydropyridine- 3-carboxamide 443.5 415 6

(S)-6-(((3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-yl)methyl) carbamoyl)picolinic acid trifluoroacetate 454.1 416 6

(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-yl)methyl)-2- oxo-1,2- dihydropyridine- 3-carboxamide 426.0 417 91

N-((3-fluoro-4- (trifluoromethoxy) phenyl)(3- fluorophenyl)methyl)-6-oxo- 1,6- dihydropyridine- 3-carboxamide 425.2 418 92

N-((2,6- difluorophenyl) (3-fluoro-4- (trifluoromethoxy) phenyl)methyl)-6-oxo-1,6- dihydropyridine- 3-carboxamide 442.8 419² 6b

(R)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-yl)methyl)-6- oxo-1,6- dihydropyridine- 3-carboxamide 425.9 420 93

N-((3-fluoro-4- (trifluoromethoxy) phenyl)(6- methoxypyridin-2-yl)methyl)-6- oxo-1,6- dihydropyridine- 3-carboxamide 438.1 421 94

N-((3-fluoro-4- trifluoromethoxy) phenyl)(5- methoxypyridin-2-yl)methyl)-6- oxo-1,6- dihydropyridine- 3-carboxamide 438.3 422 95

N-((3-fluoro-4- (trifluoromethoxy) phenyl)(4- methoxypyridin-2-yl)methyl)-6- oxo-1,6- dihydropyridine- 3-carboxamide 438.5 423 96

N-((3-fluoro-4- (trifluoromethoxy) phenyl)(4- methylpyridin-2-yl)methyl)-6- oxo-1,6- dihydropyridine- 3-carboxamide 422.0 424 97

N-((3-fluoro-4- (trifluoromethoxy) phenyl)(5- methylpyridin-2-yl)methyl)-6- oxo-1,6- dihydropyridine- 3-carboxamide 422.0 ¹Purifiedvia preparative SFC [using a Chiralpak AS-H column (250 × 21 mm, 10 μm);mobile phase 88:12 liquid CO₂:MeOH at a flow rate of 65 mL/min]resulting in Peak 1 and 2 fractions with enantiomeric excess >99%. Peak1 correlates with the (S) enantiomer example 51, peak 2 was assigned asthe (R) enantiomer. ²Purified via preparative SFC [using a ChiralpakAS-H column (150 × 21 mm, 5 μm); mobile phase 88:12 liquid CO₂: MeOH (20mM NH₃) at a flow rale of 75 mL/min] resulting in Peak 1 and 2 fractionswith enantiomeric excess >99%. Peak 1 correlates with the (S) enantiomerexample 102, peak 2 was assigned as the (R) enantiomer.

Additional Examples

Example 425(S)—N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-2-oxo-2,3-dihydrooxazolo[4,5-b]pyridine-5-carboxamide

Step 1. 3-Methoxy-6-methyl-2-nitropyridine

To a stirred mixture of 6-methyl-2-nitropyridin-3-ol (5 g, 0.032 mol,Sigma Aldrich) in DMF (50.0 mL) was added K₂CO₃ (6.72 g, 0.048 mol,S.d.fine chemicals, India). The reaction mixture was stirred for 30 minat room temperature. MeI (9 mL, 0.14 mol, Spectrochem, India) was thenadded at room temperature, and the reaction mixture was stirredovernight. After completion of the reaction (monitored by TLC, 30% EtOAcin hexane), the reaction mixture was quenched with ice water, followingwhich the solid product precipitated. The solid was collected byfiltration and washed with n-hexane to give the title compound. ¹H-NMR(400 MHz, DMSO-d₆): δ 7.88 (d, J=8.4 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H),3.92 (s, 3H), 2.44 (s, 3H). MS (ESI, positive ion) m/z: 169 (M+H).

Step 2. 5-Methoxy-6-nitropicolinic Acid

To a suspension of 3-methoxy-6-methyl-2-nitropyridine (7 g, 0.041 mol)in water (140.0 mL) was added KMnO₄ (32.88 g, 0.208 mol, S.d.finechemicals, India) at 80° C. The reaction mixture was stirred for 16 h at100° C. After completion of the reaction (monitored by TLC, 50% EtOAc inhexane), the reaction mixture was filtered and the solids were washedwith water. The filtrate was acidified and extracted with EtOAc (500mL×2). The organic layers were then dried over sodium sulfate andconcentrated under reduced pressure to afford the title compound as anoff white solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 13.6 (br. s., 1H), 8.39(d, J=8.8 Hz, 1H), 8.09 (d, J=8.8 Hz, 1H), 4.06 (s, 3H). MS (ESI,positive ion) m/z: 199 (M+H).

Step 3.(S)—N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-methoxy-6-nitropicolinamide

To a stirred solution of 5-methoxy-6-nitropicolinic acid (200 mg, 0.001mol) in DMF was added EDCI. HCl (231.6 mg, 0.0012 mol, Molekula, India)followed by HOBt (164.7 mg, 0.0012 mol, Spectrochem, India), DIPEA(521.87 mg, 0.0040 mol, Spectrochem, India) and(S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanaminehydrochloride (349.83 mg, 0.0010 mmol, Intermediate 6) at 0° C. Thereaction mixture was stirred at room temperature overnight. Aftercompletion of the reaction (monitored by TLC, 50% EtOAc in hexane),water (20 mL) was added to the reaction mixture, and the aqueoussolution was extracted with EtOAc (20 mL×2). The combined organic layerswere washed with water (100 mL×2). The organic layer was dried andconcentrated providing a residue which was purified by silica gel(60-120 mesh) column chromatography eluting with 40-50% EtOAc inpetroleum ether to give the title compound as a solid. ¹H-NMR (400 MHz,DMSO-d₆): δ 9.46 (d, J=7.6 Hz, 1H), 8.53 (d, J=4.4 Hz, 1H), 8.34 (d,J=8.4 Hz, 1H), 8.12 (d, J=8.8 Hz, 1H), 7.83 (t, J=9.6 Hz, 1H), 7.58-7.55(m, 3H), 7.35 (d, J=8.4 Hz, 1H), 6.57 (d, J=7.2 Hz, 1H), 4.04 (s, 3H).MS (ESI, positive ion) m/z: 485 (M+H).

Step 4.(S)—N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-hydroxy-6-nitropicolinamide

To a stirred solution of(S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-methoxy-6-nitropicolinamide(700 mg, 0.0011 mol) in NMP (7.0 mL) was added LiCl (183.79 mg, 0.0043mol, Sigma Aldrich, India) followed by pTSA (746.63 mg, 0.0043 mol,Sigma Aldrich, India) at room temperature. The reaction mixture wasstirred at 180° C. for 2 h. After completion of the reaction (monitoredby TLC, 100% EtOAc), the reaction mixture was cooled to room temperatureand water (50 mL) was added and the aqueous solution was extracted withEtOAc (25 mL×2). The organic extracts were washed with water (25 mL×2)and brine (25 mL) and dried over anhydrous sodium sulfate andconcentrated. The resulting material was purified by silica gel (60-120mesh) column chromatography eluting with 60-70% EtOAc in petroleum etherto give the title compound as an off-white solid. ¹H-NMR (400 MHz,DMSO-d₆): δ 12.77 (br. s., 1H), 9.43 (d, J=7.2 Hz, 1H), 8.57 (d, J=4.4Hz, 1H), 8.24 (d, J=8.4 Hz, 1H), 7.86-7.79 (m, 2H), 7.59-7.54 (m, 3H),7.37 (d, J=8.4 Hz, 1H), 6.57 (d, J=7.2 Hz, 1H). MS (ESI, positive ion)m/z: 471 (M+H).

Step 5.(S)-6-Amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-hydroxypicolinamide

To a stirred suspension of Raney Nickel (0.2 g, Monarch, India) in MeOH(10 mL), was added(S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-hydroxy-6-nitropicolinamide(200 mg, 0.0004252 mol) at room temperature. The temperature was raisedto 56° C. and hydrazine hydrate (0.2 mL, Spectrochem, India) was addedvery slowly over 5 min (exothermic reaction). The reaction mixture wasthen stirred for 10 min at the same temperature. After completion of thereaction, monitored by TLC (TLC eluent: 50% EtOAc in petroleum ether, uvactive), the mixture was cooled to room temperature, filtered throughCelite® brand filter agent and concentrated under high vacuum to removeexcess hydrazine hydrate. The resulting product was triturated withpetroleum ether to give the title compound as a grey solid. ¹H-NMR (400MHz, DMSO-d₆): δ 9.23 (d, J=8 Hz, 1H), 8.57 (d, J=4.4 Hz, 1H), 7.87 (t,J=8.8 Hz, 1H), 7.61-7.54 (m, 2H), 7.47 (d, J=11.6 Hz, 1H), 7.31 (d,J=8.4 Hz, 1H), 7.19 (d, J=8 Hz, 1H), 6.86 (d, J=8 Hz, 1H), 6.57 (d, J=8Hz, 1H), 5.53 (br. s., 2H). MS (ESI, positive ion) m/z: 441 (M+H).

Step 6.(S)—N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-2-oxo-2,3-dihydrooxazolo[4,5-b]pyridine-5-carboxamide

To a solution of(S)-6-amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-hydroxypicolinamide(300 mg, 0.681 mmol) in THF (10 mL) was added TEA (689.4 mg, 0.00068mmol, S.d fine, India) and triphosgene (242 mg, 0.0008 mmol, SigmaAldrich, India) at 0° C. The reaction mixture was stirred for 2 h atroom temperature. After completion of the reaction, monitored by TLC(TLC eluent: 50% EtOAc in petroleum ether), the reaction mixture wasquenched with sat'd NaHCO₃ solution and extracted with EtOAc (3×20 mL).The combined organic layers were washed with brine, dried over anhydroussodium sulfate, concentrated and purified by silica gel (60-120 mesh)column chromatography eluting with 80-100% EtOAc in petroleum ether toafford the title compound as an off white solid. ¹H-NMR (400 MHz,DMSO-d₆): δ 12.8 (br. s., 1H), 9.46 (d, J=7.2 Hz, 1H), 8.55 (d, J=4.4Hz, 1H), 7.83-7.77 (m, 3H), 7.57-7.49 (m, 3H), 7.33 (d, J=8.4 Hz, 1H),6.55 (d, J=6.8 Hz, 1H). MS (ESI, positive ion) m/z: 467.2 (M+H).

Example 426(S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-2-oxo-1,2-dihydrooxazolo[5,4-b]pyridine-5-carboxamide

Step 1. 2-(Benzyloxy)-6-chloro-3-nitropyridine

To a stirred mixture of 6-chloro-3-nitropyridin-2-ol (5 g, 0.0286 mol,Combi Blocks) in toluene (50.0 mL) in a 250 mL sealed tube, were addedAg₂CO₃ (11.84 g, 0.041 mol, Aldrich) and benzyl bromide (5.8 g, 0.033mol) in one lot. The reaction mixture was capped, and the mixture wasstirred for 12 h at 110° C. temperature. After completion of thereaction (monitored by TLC, 10% EtOAc in hexane), the reaction mixturewas quenched with water (50 mL) and extracted with EtOAc (50 mL×3). Theorganic layers were combined, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to give a brown solid which wasfurther purified column chromatography, silica gel (60-120 mesh) using2-6% EtOAc in petroleum ether as an eluent to obtain the title compoundas a white solid. ¹H NMR (400 MHz, CDCl₃) δ: 8.30 (d, J=8.1 Hz, 1H),7.54 (d, J=6.9 Hz, 2H), 7.42-7.26 (m, 3H), 7.09 (t, J=8.4 Hz, 1H), 5.58(s, 2H).

Step 2. 2-(Benzyloxy)-3-nitro-6-vinylpyridine

To a stirred mixture of (2-(benzyloxy)-6-chloro-3-nitropyridine (3.2 g,0.0123 mol) in toluene (32.5 mL) in a 250 mL sealed tube, were addedPd(PPh₃)₄ (426 mg, 0.000369 mol, Aldrich) and vinyl tributyltin (3.90 g,0.0123 mol). The tube was purged with the argon gas for 10 min, cappedand stirred for 12 h at 110° C. After completion of the reaction(monitored by TLC, 10% EtOAc in hexane), the reaction mixture wasquenched with water (20 mL) and extracted with EtOAc (50 mL×3). Theorganic layers were combined, dried over anhydrous sodium sulfate, andpurified by column chromatography, silica gel (60-120 mesh) using 5-7%EtOAc in petroleum ether as an eluent to afford the title compound as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.47 (d, J=8.1 Hz, 1H), 7.52(d, J=6.9 Hz, 1H), 7.43-7.27 (m, 3H), 7.20 (br. s., 2H), 6.92-6.83 (m,1H), 6.49 (dd, J=17.4, 1.5 Hz, 1H), 5.74 (dd, J=10.5, 1.5 Hz, 1H), 5.59(s, 2H). MS (ESI, positive ion) m/z: 257 (M+H).

Step 3. 6-(Benzyloxy)-5-nitropicolinaldehyde

To a cooled (0° C.) stirred mixture of(2-(benzyloxy)-3-nitro-6-vinylpyridine (0.5 g, 0.0019 mol) inacetone:water (1:1, 5 mL), was added OsO₄ (16.39 mg, 0.000064 mol,Aldrich) and NaIO₄ (1.67 g, 0.0078 mol, Aldrich). The reaction mixturewas stirred for 4 h at room temperature. After completion of thereaction (monitored by TLC, 10% EtOAc in hexane), the reaction mixturewas quenched with water (10 mL) and extracted with EtOAc (5 mL×3). Theorganic layers were combined, dried over anhydrous sodium sulfate andpurified by column chromatography, silica gel (60-120 mesh) using 5-7%EtOAc in petroleum ether as an eluent to afford the title compound. ¹HNMR (400 MHz, CDCl₃) δ: 10.00 (s, 1H), 8.38 (d, J=6 Hz, 1H), 7.69 (d,J=6 Hz, 1H), 7.54 (d, J=5.7 Hz, 2H), 7.41-7.37 (m, 3H), 5.69 (s, 2H).

Step 4. 6-(Benzyloxy)-5-nitropicolinic Acid

To a cooled (0° C.) stirred mixture of6-(benzyloxy)-5-nitropicolinaldehyde (0.5 g, 0.0019 mol) inacetone:water (1:1, 5 mL), was added sulphamic acid (280 mg, 0.00029mol, Aldrich) and NaClO₂ (260 mg, 0.00029 mol, Aldrich). The reactionmixture was stirred for 2 h at the same temperature. After completion ofthe reaction (monitored by TLC, 10% EtOAc in hexane), the reactionmixture was quenched with water (2 mL) and extracted with EtOAc (20mL×3). The organic layers were combined, dried over anhydrous sodiumsulfate, and purified by column chromatography, silica gel (60-120 mesh)using 5-9% EtOAc in petroleum ether as an eluent to give the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ: 13.80 (br. s., 1H), 8.45 (d, J=8.1Hz, 1H), 7.96 (d, J=8.1 Hz, 1H), 7.51 (d, J=7.2 Hz, 2H), 7.44-7.36 (m,3H), 5.62 (s, 2H).

Step 5.(S)-6-(Benzyloxy)-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-nitropicolinamide

To a stirred solution of 6-(benzyloxy)-5-nitropicolinic acid (500 mg,0.0018 mol) in DMF (10 mL), were added(S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanaminehydrochloride (620 mg, 0.0018 mol, Intermediate 6), HATU (1 g, 0.0029mol) and DIPEA (700 mg, 0.0054 mol). The reaction mixture was thenstirred for 12 h at room temperature. Progress was monitored by TLC(100% EtOAc). After completion of reaction, water (100 mL) was added andproduct was extracted with EtOAc (50 mL×3) and concentrated to obtainthe product which was purified by column chromatography, silica gel(100-200 mesh), using 80-100% EtOAc in petroleum ether as the eluent toafford the title compound ¹H NMR (400 MHz, DMSO-d₆) δ: 9.75 (d, J=7.6Hz, 1H), 8.61-8.56 (m, 2H), 7.79 (d, J=8.4 Hz, 2H), 7.59-7.54 (m, 5H),7.35-7.32 (m, 4H), 6.60 (d, 1H), 5.77 (s, 2H).

Step 6.(S)-5-Amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-6-hydroxypicolinamide

To a stirred mixture of(S)-6-(benzyloxy)-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-nitropicolinamide(800 mg, 0.0014 mol) in THF (8 mL), was added 10% Pd/C (800 mg,Aldrich). The reaction mixture was stirred under hydrogen atmosphere inthe form of hydrogen bladder (˜20-22 PSI) for 12 h at room temperature.After completion of the reaction (monitored by TLC, 100% EtOAc), thereaction mixture was filtered through Celite® brand filter agent, thefiltrate dried over anhydrous sodium sulfate and concentrated underreduced pressure to afford the title compound. ¹H NMR (400 MHz, DMSO-d₆)δ: 11.00 (s, 1H), 9.13 (d, J=6 Hz, 1H), 8.46 (d, J=4 Hz, 1H), 7.79 (t,J=9.2 Hz, 1H), 7.57-7.46 (m, 3H), 7.33 (d, J=8.4 Hz, 1H), 7.08 (br. s.,1H), 6.62 (d, J=7.6 Hz, 1H), 6.40 (br. s., 1H), 5.83 (br. s., 2H). MS(ESI, positive ion) m/z: 440.9 (M+H).

Step 7.(S)—N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-2-oxo-1,2-dihydrooxazolo[5,4-b]pyridine-5-carboxamide

To a cooled (−78° C.), stirred mixture of(S)-5-amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-6-hydroxypicolinamide(400 mg, 0.00098 mol) in THF (4 mL) was added TEA (1.31 mL, 0.0090 mol,Spectrochem, India) and triphosgene (323 mg, 0.0010 mol, Spectrochem,India) in one lot and the reaction mixture was stirred for 2 h at thesame temperature. The reaction was slowly warmed to room temperatureovernight. After completion of the reaction (monitored by TLC, 50% EtOAcin hexane), the reaction mixture was quenched with water (2 mL) andextracted with EtOAc (2 mL×3). The combined organic layers were driedover anhydrous sodium sulfate and purified by column chromatography,silica (60-120 mesh) using 50-60% EtOAc in petroleum ether as an eluent,and subsequently purified further using Prep TLC plates, mobile phase50% EtOAc in hexane to give the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ: 12.40 (s, 1H), 9.53 (d, J=7.2 Hz, 1H), 8.59 (d, J=4.4 Hz,1H), 7.90-7.80 (m, 2H), 7.61-7.53 (m, 4H), 7.35 (d, J=8.8 Hz, 1H), 6.54(d, J=7.2 Hz, 1H). MS (ESI, positive ion) m/z: 467.1 (M+H).

Example 427(S)—N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-2-oxo-2,3-dihydrooxazolo[4,5-b]pyridine-6-carboxamide

Step 1. Ethyl 5-hydroxynicotinate

To a stirred mixture of 5-hydroxynicotinic acid (25 g, 0.1797 mol, CombiBlocks) in EtOH (500 mL) was added a catalytic amount of conc. H₂SO₄.The resulting reaction mixture was stirred for 12 h at 110° C. Aftercompletion of the reaction (monitored by TLC, 10% MeOH in CHCl₃), EtOHwas removed under reduced pressure and the reaction mixture was quenchedwith sat'd NaHCO₃ solution (50 mL) and extracted with EtOAc (50 mL×3).The combined organic layers were dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford the title compound as asolid. ¹H NMR (400 MHz, CDCl₃) δ: 11.00 (br.s., 1H), 8.74 (s, 1H), 8.42(d, J=2.1 Hz, 1H), 7.90 (t, J=3.9 Hz, 1H), 4.43 (q, J=7.2 Hz, 2H), 1.43(t, J=6.9 Hz, 3H). MS (ESI, positive ion) m/z: 168 (M+H).

Step 2. Ethyl 6-chloro-5-hydroxynicotinate

To a stirred mixture of ethyl 5-hydroxynicotinate (20 g, 0.119 mol, inDMF (200.0 mL) was added NCS (19.18 g, 0.143 mol, Aldrich). The reactionmixture was stirred for 2 h at 80° C. After completion of the reaction(monitored by TLC, 30% EtOAc in hexane), the reaction mixture wasquenched with sat'd NaHCO₃ solution (50 mL) and extracted with EtOAc(500 mL×3). The combined organic layers were dried over anhydrous sodiumsulfate, and purified by column chromatography, silica gel (100-200mesh), using 10-15% EtOAc in petroleum ether as the eluent to give thetitle compound as a solid. ¹H NMR (400 MHz, CDCl₃) δ: 8.61 (d, J=2.1 Hz,1H), 7.92 (d, J=1.8 Hz, 1H), 5.94 (br. s., 1H), 4.53 (q, J=6.9 Hz, 2H),1.43 (t, J=7.2 Hz, 3H). MS (ESI, positive ion) m/z: 202.1 (M+H).

Step 3. Ethyl 5-(benzyloxy)-6-chloronicotinate

To a stirred mixture of ethyl 6-chloro-5-hydroxynicotinate (2 g, 0.01mol) in Toluene (50.0 mL) were added K₂CO₃ (2.76 g, 0.02 mol, Rankem,India) and benzyl bromide (2 g, 0.0012 mol). The reaction mixture wasstirred for 2 h at room temperature. After completion of the reaction(monitored by TLC, 20% EtOAc in hexane), the reaction mixture wasquenched with water (50 mL), extracted with EtOAc (50 mL×3). Thecombined organic layers were dried over anhydrous sodium sulfate andpurified by column chromatography, silica gel (60-120 mesh) using 12-16%EtOAc in petroleum ether as the eluent to give the title compound. MS(ESI, positive ion) m/z: 292.2 (M+H).

Step 4. Ethyl 5-(benzyloxy)-6-((tert-butoxycarbonyl)amino)nicotinate

To a stirred mixture of ethyl 5-(benzyloxy)-6-chloronicotinate (2.1 g,0.00719 mol) in THF (21 mL) in a 250 mL sealed tube, were addedPd₂(dba)₃ (395 mg, 0.00043 mol, Aldrich), NH₂Boc (1.68 g, 0.0143 mol,Aldrich), X-phos (500 mg, 0.0010 mol, Aldrich) and K₃PO₄ (4.5 g, 0.0010mol). The vessel was purged with argon gas for 10 min. The reactionmixture was then stirred for 12 h at 80° C. After completion of thereaction (monitored by TLC, 30% EtOAc in hexane), the reaction mixturewas quenched with water (50 mL) and extracted with EtOAc (50 mL×3). Thecombined organic layers were dried over anhydrous sodium sulfate, andpurified by column chromatography, silica gel (60-120 mesh) using 23-30%EtOAc in petroleum ether as the eluent to give the title compound. ¹HNMR (400 MHz, DMSO-d₆) δ: 9.22 (s, 1H), 8.46 (d, J=1.8 Hz, 1H), 7.81 (d,J=1.8 Hz, 1H), 7.53 (d, J=6.6 Hz, 2H) 7.42-7.33 (m, 3H), 5.22 (s, 2H),4.36 (q, J=6.9 Hz, 2H), 1.44 (s, 9H), 1.36 (t, 3H).

Step 5. 5-(Benzyloxy)-6-((tert-butoxycarbonyl)amino)nicotinic Acid

To a cooled (0° C.) stirred mixture of ethyl5-(benzyloxy)-6-((tert-butoxycarbonyl)amino)nicotinate (1.2 g, 0.0032mol) in EtOH:water (1:1, 12 mL), was added LiOH (154 mg, 0.0064 mol,Aldrich). The reaction mixture was stirred for 2 h at room temperature.After completion of the reaction (monitored by TLC, 100% EtOAc), thereaction mixture was quenched with 1N HCl at 0° C. temperature andextracted with EtOAc (2 mL×3). The combined organic layers were driedover anhydrous sodium sulfate and concentrated under reduced pressure togive the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ: 13.24 (s, 1H),9.18 (s, 1H), 8.45 (d, J=1.2 Hz, 1H), 7.80 (d, J=1.5, Hz, 1H), 7.53 (d,J=5.4 Hz, 2H), 7.41-7.34 (m, 2H), 5.24 (s, 2H), 1.38 (s, 9H).

Step 6. (S)-tert-Butyl(2-(benzyloxy)-5-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)pyridin-3-yl)carbamate

To a stirred solution of5-(benzyloxy)-6-((tert-butoxycarbonyl)amino)nicotinic acid (800 mg,0.0023 mol) in DMF (10 mL), were added(S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanaminehydrochloride (790 mg, 0.0023 mol, Intermediate 6), HATU (1.325 g,0.0034 mol) and DIPEA (900 mg, 0.0069 mol). The reaction mixture wasthen stirred for 12 h at rt. Reaction progress was monitored by TLC(100% EtOAc). After completion of the reaction, water (8 mL) was added,and the aqueous solution was extracted with EtOAc (5 mL×3) andconcentrated to provide the product. The product thus obtained waspurified by column chromatography, silica gel (100-200 mesh), using80-100% EtOAc in petroleum ether as the eluent to give the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ: 9.52 (d, J=7.6 Hz, 1H), 9.10 (s,1H), 8.47 (t, 7.5 Hz, 2H), 7.93 (d, J=1.8 Hz, 1H), 7.82 (dd, 0.9, 9.6Hz, 1H), 7.63-7.46 (m, 4H), 7.40-7.33 (m, 4H), 6.75 (d, J=7.8 Hz, 1H),5.20 (s, 2H), 1.40 (s, 9H).

Step 7. ((S)-tert-Butyl(5-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)-2-hydroxypyridin-3-yl)carbamate

To a stirred mixture of (S)-tert-butyl(2-(benzyloxy)-5-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)pyridine)-carbamate(800 mg, 0.0012 mol) in THF (8 mL) was added 10% Pd/C (800 mg, Aldrich).The reaction mixture was stirred under a hydrogen atmosphere in the formof a hydrogen bladder (˜20-22 PSI) for 12 h at room temperature. Aftercompletion of the reaction (monitored by TLC, 100% EtOAc), the reactionmixture was filtered through Celite® brand filter agent. The filtratewas dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ:10.40 (br. s., 1H), 9.42 (d, J=7.8 Hz, 1H), 9.01 (s, 1H), 8.45 (d, J=4.8Hz, 1H), 8.35 (d, J=1.8 Hz, 1H), 7.95 (s, 1H), 7.80 (t, 9.6 Hz, 1H),7.61-7.45 (m, 4H), 7.37 (d, 8.4 Hz, 1H), 1.44 (s, 9H). MS (ESI, positiveion) m/z: 541 (M+H).

Step 8.(S)-5-Amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-6-hydroxynicotinamide

To a stirred mixture of ((S)-tert-butyl(5-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)-2-hydroxypyridin-3-yl)carbamate(600 mg, 0.0011 mol), in DCM (6 mL) was added TFA (1.2 mL, 0.143 mol,Aldrich). The resulting mixture was then stirred for 2 h at roomtemperature. After completion of the reaction (monitored by TLC, 30%EtOAc in hexane), the reaction mixture was quenched with sat'd NaHCO₃solution (50 mL) and extracted with EtOAc (50 mL×3). The combinedorganic layers were dried over anhydrous sodium sulfate and concentratedunder reduced pressure to afford the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ: 9.78 (s., 1H), 9.00 (d, J=7.8 Hz, 1H), 8.44 (d, J=4.8 Hz,1H), 8.13 (d, J=1.8 Hz, 1H), 7.79 (dd, J=1.2, 9.9 Hz, 1H), 7.60-7.43 (m,3H), 7.35 (d, 8.7 Hz, 1H), 7.26 (d, J=1.8 Hz, 1H), 6.66 (d, J=7.8 Hz,1H), 6.18 (br.s., 2H). MS (ESI, positive ion) m/z: 441.1 (M+H).

Step 9.(S)—N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-2-oxo-2,3-dihydrooxazolo[4,5-b]pyridine-6-carboxamide

To a cooled (−78° C.) stirred mixture of(S)-5-amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-6-hydroxynicotinamide(400 mg, 0.00098 mol) in THF (4 mL), were added TEA (1.31 mL, 0.0090mol, Spectrochem, India) and triphosgene (323 mg, 0.0010 mol,Spectrochem, India). The reaction mixture was stirred for 2 h at thesame temperature. The reaction was then slowly warmed to roomtemperature overnight. After completion of the reaction (monitored byTLC, 50% EtOAc in hexane), the reaction mixture was quenched with water(2 mL) and extracted with EtOAc (2 mL×3). The combined organic layerswere dried over anhydrous sodium sulfate, and purified by columnchromatography, silica gel (60-120 mesh) using 50-60% EtOAc in petroleumether as an eluent, and purified again using Prep TLC plates, mobilephase 50% EtOAc in hexane to afford the title compound. ¹H NMR (400 MHz,CD₃OD) δ: 8.58 (s., 1H), 8.48 (d, J=4.8 Hz, 1H), 7.89 (s, 1H), 7.65 (t,J=9.6 Hz, 1H), 7.46-7.32 (m, 4H), 6.68 (s, 2H). MS (ESI, positive ion)m/z: 467 (M+H).

Example 428(S)-2-(5-(((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)-2-oxopyridin-1(2H)-yl)aceticAcid

Step 1. Benzyl 2-oxo-2H-pyran-5-carboxylate

A solution of coumalic acid (1.2 g, 8.57 mmol) in DCM (20 mL) and THF(20 mL) was treated with 4-dimethylaminopyridine (0.105 g, 0.857 mmol).The reaction was stirred under nitrogen at 23° C. After 15 min, benzylalcohol (0.886 mL, 8.57 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.642 g,8.57 mmol) were added, and the stirring was continued. After 5 h, thesolution was diluted with DCM (200 mL) and the mixture was washed withwater (150 mL), dried over MgSO₄, concentrated in vacuo and purified bysilica gel chromatography (eluent: 5-25% EtOAc/hexane), affording thetitle compound as a white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.32 (s,1H), 7.80 (dd, J=9.78, 2.15 Hz, 1H), 7.33-7.48 (m, 5H), 6.33 (d, J=9.78Hz, 1H), 5.31 (s, 2H). MS (ESI, positive ion) m/z: 231.1 (M+H).

Step 2. Benzyl1-(2-(tert-butoxy)-2-oxoethyl)-6-oxo-1,6-dihydropyridine-3-carboxylate

A solution of benzyl 2-oxo-2H-pyran-5-carboxylate (906 mg, 3.94 mmol)and glycine tert butyl ester hydrochloride (726 mg, 4.33 mmol) in MeOH(20 mL) was treated with TEA (1.642 mL, 11.81 mmol). The reaction wasstirred at 23° C. under nitrogen. After 1 h, the solution wasconcentrated in vacuo and purified by silica gel chromatography (eluent:10-50% EtOAc/hexane), affording the title compound as a light yellowoil. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.11 (d, J=2.35 Hz, 1H), 7.90 (dd,J=9.59, 2.54 Hz, 1H), 7.31-7.54 (m, 5H), 6.55 (d, J=9.59 Hz, 1H), 5.30(s, 2H), 4.56 (s, 2H), 1.48 (s, 9H). MS (ESI, positive ion) m/z: 366.0(M+H).

Step 3.1-(2-(tert-Butoxy)-2-oxoethyl)-6-oxo-1,6-dihydropyridine-3-carboxylicAcid

A solution of benzyl1-(2-(tert-butoxy)-2-oxoethyl)-6-oxo-1,6-dihydropyridine-3-carboxylate(924 mg, 2.69 mmol) in EtOAc (20 mL) and EtOH (5 mL) was treated withpalladium 10 wt. % on activated carbon (143 mg, 0.135 mmol) undernitrogen. The reaction vessel was purged through 3 vacuum-hydrogencycles, and was stirred under a hydrogen balloon at 23° C. After 45 min,the reaction was filtered through Celite® brand filter agent, the filtercake washed with MeOH (100 mL), the filtrates were combined andconcentrated, affording the title compound as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 12.02-13.68 (br. s., 1H), 8.49 (br. s., 1H), 7.83(d, J=9.39 Hz, 1H), 6.44 (d, J=9.19 Hz, 1H), 4.68 (br. s., 2H), 1.41 (s,9H). MS (ESI, positive ion) m/z: 276.0 (M+H).

Step 4. (S)-tert-Butyl2-(5-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)-2-oxopyridin-1(2H)-yl)acetate

A solution of(S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanaminehydrochloride (400 mg, 1.174 mmol, Intermediate 6),1-(2-(tert-butoxy)-2-oxoethyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (327 mg, 1.292 mmol) and HATU (491 mg, 1.292 mmol) in DMF (10 mL)was treated with TEA (0.490 mL, 3.52 mmol). The reaction was thenstirred at 23° C. under nitrogen. After 17 h, the solution was dilutedwith EtOAc (100 mL) and washed with brine (100 mL), dried over MgSO₄,concentrated in vacuo and purified by silica gel chromatography (eluent:5-30% EtOAc/DCM), affording the title compound as a colorless oil. Thecompound was taken forward to the next step. MS (ESI, positive ion) m/z:540.2 (M+H).

Step 5.(S)-2-(5-(((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)-2-oxopyridin-1(2H)-yl)aceticAcid

A mixture of (S)-tert-butyl2-(5-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)-2-oxopyridin-1(2H)-yl)acetate(633 mg, 1.173 mmol) and silica gel 60 (70.5 mg, 1.173 mmol) in toluene(10 mL) was heated to 110° C. After 3 h, the reaction was cooled to 23°C. and filtered. The residue was washed with 10% MeOH/DCM (100 mL), andthe filtrates were combined and concentrated affording the titlecompound as a tan solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.08 (d, J=7.8Hz, 1H), 8.44 (br. s., 2H), 7.87-8.02 (m, 1H), 7.76 (s, 1H), 7.42-7.63(m, 3H), 7.34 (d, J=8.4 Hz, 1H), 6.66 (d, J=7.4 Hz, 1H), 6.41 (d, J=9.6Hz, 1H), 4.57 (d, J=3.7 Hz, 2H). MS (ESI, positive ion) m/z: 484.1(M+H).

Example 429(S)-2-(5-(((3-Fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamoyl)-2-oxopyridin-1(2H)-yl)aceticAcid

This compound was prepared by the same method as Example 428 employingamine intermediate 2 in Step 4. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.10 (d,J=7.6 Hz, 1H), 8.45 (br. s., 2H), 7.94 (dd, J=9.4, 2.3 Hz, 1H),7.67-7.83 (m, 3H), 7.61 (d, J=8.0 Hz, 2H), 7.47 (dt, J=8.5, 4.3 Hz, 1H),6.71 (d, J=7.6 Hz, 1H), 6.40 (d, J=9.6 Hz, 1H), 4.54 (d, J=4.1 Hz, 2H).MS (ESI, positive ion) m/z: 450.0 (M+H).

Example 430(S)—N-((3-Ethylpyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide

To a 100 mL round bottom flask containing(S)-6-oxo-N-((4-(trifluoromethyl)phenyl)(3-vinylpyridin-2-yl)methyl)-1,6-dihydropyridine-3-carboxamide(40 mg, 0.100 mmol, Example 363) was added EtOAc (20 mL). The resultingmixture was then stirred at 23° C. for 2 min. At this time, Pd/C (10%,20 mg) was added before a balloon of hydrogen was bubbled through themixture. The reaction was stirred for 2 h under hydrogen (1 atm) and wasthen filtered though a plug of Celite® brand filter agent and elutedwith EtOAc (50 mL). The solvent was removed, and the material was placedon high vacuum for 1 h to give the title compound as a white solid. ¹HNMR (400 MHz, CDCl₃) δ ppm 8.67 (d, J=6.9 Hz, 1H), 8.53 (d, J=4.7 Hz,1H), 8.07 (d, J=2.2 Hz, 1H), 7.94 (dd, J=9.6, 2.4 Hz, 1H), 7.36-7.67 (m,5H), 7.27-7.36 (m, 1H), 6.60 (d, J=9.5 Hz, 1H), 6.50 (d, J=6.7 Hz, 1H),2.63-2.82 (m, 1H), 2.36-2.62 (m, 1H), 1.11 (t, J=7.5 Hz, 3H). MS (ESI,positive ion) m/z: 402.1 (M+H).

Example 431(S)-2-Amino-4-(((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamoyl)phenylAcetate

Step 1.(S)—N-((3-Fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-4-hydroxy-3-nitrobenzamide

To a solution of 4-hydroxy-3-nitrobenzoic acid (285 mg, 1.556 mmol) andDMF (5 mL), were added DIPEA (0.69 mL, 3.96 mmol) and HATU (612 mg,1.611 mmol). After stirring for 45 min,(S)-(3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methanaminehydrochloride (380 mg, 1.239 mmol, Intermediate 2) was added in oneportion. The reaction was stirred at room temperature for 5 h and wasthen diluted with water (50 mL). The aqueous solution was extracted withEtOAc (3×20 mL). The combined EtOAc layers were concentrated in vacuoand adsorbed onto a plug of silica gel and chromatographed through aRedi-Sep® pre-packed silica gel column (12 g), eluting with 0 to 75%EtOAc in hexane, to provide the title compound as a yellow solid. MS(ESI pos. ion) m/z: 436.1 (M+H).

Step 2.(S)-4-(((3-Fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamoyl)-2-nitrophenylAcetate

To a solution of(S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-4-hydroxy-3-nitrobenzamide(83 mg, 0.191 mmol) and DCM (5 mL) were added acetic anhydride (0.2 mL,2.120 mmol) and DIPEA (0.15 mL, 0.861 mmol). After stirring for 45 min,the reaction was quenched with water and after stirring for 3 days, theaqueous solution was filtered to give the title compound as a yellowsolid. The resulting product was used in the next step without furtherpurification. MS (ESI pos. ion) m/z: 478.1 (M+H).

Step 3.(S)-2-Amino-4-(((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamoyl)phenylAcetate

To a round bottom flask purged with N₂ was added 10% Pd/C (20.29 mg,0.019 mmol) and under a N₂ atmosphere(S)-4-(((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamoyl)-2-nitrophenylacetate (91 mg, 0.191 mmol) in EtOAc (10 mL) was added. The solution waspurged for a further 2 min, then capped with a balloon of H₂. After 5 h,the reaction was filtered through a pad of Celite® brand filter agentand the Celite® brand filter agent rinsed with EtOAc. The filtrate wasconcentrated in vacuo and adsorbed onto a plug of silica gel andchromatographed through a Redi-Sep® pre-packed silica gel column (4 g),eluting with 0 to 75% EtOAc in hexane, to provide the title compound asa white solid. ¹H NMR (300 MHz, CDCl₃) δ ppm 9.85 (s, 1H), 8.35-8.54 (m,2H), 8.19 (s, 1H), 7.66 (d, J=2.2 Hz, 1H), 7.59 (dd, J=8.5, 2.0 Hz, 1H),7.55 (s, 4H), 7.38-7.47 (m, 1H), 7.32 (dt, J=8.4, 4.3 Hz, 1H), 7.04 (d,J=8.3 Hz, 1H), 6.62 (dd, J=6.9, 2.0 Hz, 1H), 2.20 (s, 3H). MS (ESI pos.ion) m/z: 448.1 (M+H).

Example 432(S)-4-(((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)benzoicAcid

Step 1. (S)-Methyl4-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)benzoate

To a solution of(S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanaminehydrochloride (100 mg, 0.294 mmol, Intermediate 6),4-(methoxycarbonyl)benzoic acid (52.9 mg, 0.294 mmol), and DMF (2 mL)were added TEA (0.123 mL, 0.881 mmol) and 50% propylphosphonic anhydridein EtOAc (0.175 mL, 0.587 mmol). The solution was stirred at roomtemperature. After 2 h, the reaction was diluted with water (30 mL),stirred for 30 min, and then filtered. The solids were washed with waterand dried in the funnel to give the title compound as a white solid. MS(ESI pos. ion) m/z: 467.0 (M+H).

Step 2.(S)-4-(((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)benzoicAcid

To a solution of (S)-methyl4-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)benzoate(105 mg, 0.225 mmol) and THF (2 mL):MeOH (1 mL) was added 1M LiOH (1mL). The solution was stirred at room temperature. After 16 h, thereaction was diluted with water. The aqueous solution was acidified with1 N HCl to a pH of 7 and extracted with EtOAc (3×15 mL). The combinedEtOAc layers were dried over MgSO₄ and concentrated in vacuo to give thetitle compound as a white solid. ¹H NMR (300 MHz, MeOH-d4) δ ppm 8.49(d, J=4.7 Hz, 1H), 8.06-8.15 (m, J=8.5 Hz, 2H), 7.89-8.00 (m, J=8.5 Hz,2H), 7.64 (t, J=9.1 Hz, 1H), 7.31-7.51 (m, 4H), 6.70 (s, 1H). MS (ESIpos. ion) m/z: 453.0 (M+H).

Example 433(S)—N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)imidazo[1,2-a]pyridine-6-carboxamide

To a solution of(S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanaminehydrochloride (81 mg, 0.238 mmol, Intermediate 6) and EtOAc (3 mL) wasadded 50% propylphosphonic anhydride in EtOAc (0.28 mL, 0.470 mmol),imidazo[1,2-a]pyridine-6-carboxylic acid (47 mg, 0.290 mmol) and DIPEA(0.12 mL, 0.689 mmol). The solution was stirred at room temperature.After 16 h, the reaction product was adsorbed onto a plug of silica geland chromatographed through a Redi-Sep® pre-packed silica gel column (4g), eluting with 0 to 100% EtOAc in hexane, to provide the titlecompound as a white solid. ¹H NMR (300 MHz, MeOH-d4) δ ppm 9.06-9.16 (m,1H), 8.44-8.55 (m, 1H), 7.96 (s, 1H), 7.76 (dd, J=9.5, 1.8 Hz, 1H),7.56-7.71 (m, 3H), 7.42-7.51 (m, 2H), 7.32-7.42 (m, 2H), 6.68-6.76 (m,1H). MS (ESI pos. ion) m/z: 449.0 (M+H).

Example 434(S)-6-(((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)nicotinicAcid

Step 1. (S)-Methyl6-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)nicotinate

To a solution of(S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanaminehydrochloride (17.0 g, 49.9 mmol, Intermediate 6) in DMF (166 mL,Aldrich) was added 5-(methoxycarbonyl)pyridine-2-carboxylic acid (9.94g, 54.9 mmol, Oakwood Products, Inc.), HATU (20.87 g, 54.9 mmol, AccelaChemBio, Inc.), and DIPEA (18.23 mL, 105 mmol, EMD Biosciences, Inc.).The resulting mixture was then stirred at room temperature for 18 h.Water (400 mL) was then added and the mixture was extracted with EtOAc(2×200 mL). The combined organic extracts were dried over MgSO₄ andconcentrated in vacuo. The residue was then dissolved in MeOH (500 mL)and silica gel was added. The mixture was concentrated and dried invacuo. The solid mixture was purified by silica gel flash columnchromatography using ISCO instrument (solid loading, 0-100%EtOAc/hexane) to give the title compound as a white solid. MS (ESI,positive ion) m/z: 468 (M+H).

Step 2.(S)-6-(((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)nicotinicAcid

To a solution of (S)-methyl6-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)nicotinate(11.5 g, 24.61 mmol) in MeOH (140 mL, Aldrich) was added lithiumhydroxide hydrate (2.065 g, 49.2 mmol, Aldrich). The mixture was stirredat room temperature for 5 min followed by the addition of THF (5 mL,Aldrich) and the mixture was stirred at room temperature for 1 h. Themixture was concentrated in vacuo, cooled to 0° C. and was adjusted topH=6-7 with concentrated HCl. EtOAc (300 mL) was added to the adjustedpH mixture, and the resulting mixture was stirred at room temperaturefor 15 min. The organic layer was collected and the aqueous phase wasextracted with EtOAc (1×200 mL). The combined organic layers were driedover MgSO₄ and concentrated in vacuo. The residue was then dissolved inMeOH (400 mL) and silica gel was added. The mixture was concentrated anddried in vacuo. The solid mixture was then purified by silica gel flashcolumn chromatography using ISCO instrument (solid loading, 40%EtOAc/hexane, then 10% MeOH in EtOAc) to give the title compound as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.75 (br. s., 1H), 9.85(d, J=7.4 Hz, 1H), 9.18 (d, J=1.4 Hz, 1H), 8.58 (d, J=4.7 Hz, 1H), 8.48(dd, J=8.1, 2.1 Hz, 1H), 8.16 (d, J=8.0 Hz, 1H), 7.83 (t, J=9.3 Hz, 1H),7.50-7.61 (m, 3H), 7.36 (d, J=8.4 Hz, 1H), 6.58 (d, J=7.2 Hz, 1H). MS(ESI, positive ion) m/z: 454.0 (M+H)

Example 435(R)-6-(((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)nicotinicAcid

This compound was prepared using the same procedure as example 434,except the use of Intermediate 6b in Step 1. The compound was purifiedvia preparative SFC [using a Chiralpak AS-H column (250×21 mm, 5 μm);mobile phase 92:8 liquid CO₂:EtOH with 0.2% diethylamine at a flow rateof 70 mL/min] resulting in Peak 1 and 2 fractions with enantiomericexcess >99%. Peak 2 correlates with the (S) enantiomer (example 434),peak 1 was assigned as the (R) enantiomer. ¹H NMR (400 MHz, DMSO-d₆) δppm 9.78 (d, J=7.6 Hz, 1H), 9.05 (s, 1H), 8.59 (d, J=4.7 Hz, 1H), 8.31(dd, J=7.9, 1.7 Hz, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.82 (t, J=9.2 Hz, 1H),7.49-7.61 (m, 3H), 7.35 (d, J=8.6 Hz, 1H), 6.57 (d, J=7.0 Hz, 1H). MS(ESI, positive ion) m/z: 454.1 (M+H)

Example 436(S)—N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-1-hydroxy-4-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxamide

Step 1.(S)—N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-3-(methylamino)-4-nitrobenzamide

To a solution of(S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanaminehydrochloride (1.0 g, 2.94 mmol, intermediate 6) in DMF (20 mL, Aldrich)was added 3-fluoro-4-nitrobenzenecarboxylic acid (0.543 g, 2.94 mmol,Bionet Research (A Trading Division of Key Organics Ltd)), HATU (1.228g, 3.23 mmol, Oakwood Products, Inc.), and DIPEA (1.123 mL, 6.46 mmol,EMD Biosciences, Inc.). The resulting mixture was then stirred at roomtemperature for 1 h. The mixture was transferred to a pressure tube, andmethylamine, 2.0M solution in THF (7.34 mL, 14.68 mmol, Aldrich) andDIPEA (1.123 mL, 6.46 mmol, EMD Biosciences, Inc.) were added. Theresulting mixture was heated at 55° C. for 18 h, then cooled to roomtemperature. Water (150 mL) was added and the mixture was extracted withEtOAc (2×150 mL). The combined organic extracts were dried over MgSO₄and concentrated in vacuo. The residue was dissolved in DCM and thesolution mixture was purified by silica gel flash column chromatographyusing ISCO instrument (0-100% EtOAc/hexane) to give the title compoundas a yellow solid. MS (ESI, positive ion) m/z: 483 (M+H).

Step 2. (S)-Methyl2-((5-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)-2-nitrophenyl)(methyl)amino)-2-oxoacetate

To a solution of(S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-3-(methylamino)-4-nitrobenzamide(1.28 g, 2.65 mmol) and DIPEA (0.462 mL, 2.65 mmol, EMD Biosciences,Inc.) in DCM (7 mL, Aldrich) at 0° C. was added methyl chloro oxoacetate(0.268 mL, 2.92 mmol, Aldrich) in a drop-wise fashion. The resultingmixture was stirred at 0° C. for 2 h. Water (20 mL) was added, and themixture was stirred at room temperature for 5 min. The organic layer wascollected, and the aqueous layer was extracted with EtOAc (1×20 mL). Thecombined organic layers were dried over MgSO₄ and concentrated in vacuo.The residue was dissolved in DCM, and the mixture was purified by silicagel column chromatography using ISCO instrument (35-100% EtOAc/hexane)to give the title compound as a yellow solid. MS (ESI, positive ion)m/z: 569 (M+H).

Step 3.(S)—N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-1-hydroxy-4-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxamide

To a solution of (S)-methyl2-((5-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)-2-nitrophenyl)(methyl)amino)-2-oxoacetate(0.500 g, 0.880 mmol) in MeOH (3 mL, Aldrich), was added palladium, 10wt. % (dry basis) on activative carbon, wet, degussa type (0.047 g,0.440 mmol, Aldrich). The resulting mixture was stirred at roomtemperature under hydrogen (balloon) for 4 h. The mixture was filteredthrough celite and the celite was washed with MeOH (2×10 mL). Thecombined filtrates were concentrated in vacuo. Dioxane (3.00 mL,Aldrich) and water (1 mL) were added, followed by potassium phosphate(0.560 g, 2.64 mmol, Strem Chemical). The mixture was heated at 90° C.for 18 h. The mixture was then cooled to room temperature and filtered.The solid was washed with water (2×30 mL) and dried in vacuo to affordthe title compound as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm9.37 (d, J=7.8 Hz, 1H), 8.47 (d, J=4.5 Hz, 1H), 7.93 (br. s., 1H),7.74-7.84 (m, 3H), 7.55-7.67 (m, 2H), 7.50 (dt, J=8.5, 4.3 Hz, 1H), 7.40(d, J=8.4 Hz, 1H), 6.78 (d, J=7.8 Hz, 1H), 3.52-3.66 (m, 3H). MS (ESI,positive ion) m/z: 523 (M+H).

Example 437(S)—N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-2-oxo-1,2-dihydrooxazolo[5,4-c]pyridine-6-carboxamide

Step 1. 5-Methoxy-2-methylpyridine

To a stirred solution of 60% NaH (in mineral oil) (18.27 g, 0.458 mol,Aldrich, India) in DMSO (66 mL, Spectrochem., India) at 0° C., was added6-methylpyridin-3-ol (25.0 g, 0.229 mol) dissolved in DMSO (100 mL) dropwise over a period of 15 min. After complete addition, the reactionmixture was stirred at 0° C. for 40 min. Methyl iodide (29.5 mL, 0.458mol, Spectrochem, India) was added and the reaction mixture was stirredat rt for 2 h. The reaction with water and Et₂O (1:1, 200 mL). Theorganic layer was separated and aqueous layer was back extracted withEt₂O (75 mL×3). The organic layers were combined, dried over anhydroussodium sulfate and concentrated to give the title compound as a darkbrown gummy oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.19 (d, J=2.8 Hz, 1H),7.12-7.05 (m, 2H), 3.83 (s, 3H), 2.49 (s, 3H). MS (ESI, positive ion)m/z: 124.0 (M+H).

Step 2. 5-Methoxy-2-methylpyridine 1-oxide

To a stirred solution of 5-methoxy-2-methylpyridine (15 g, 0.121 mol) inDCM (200 mL) was added 3-chloro peroxybenzoic acid (23.14 g, 0.134 mol,Aldrich). The reaction was stirred at rt for 3 h. Reaction progress wasmonitored by TLC (50% EtOAc in petroleum ether). After completion ofreaction, the reaction mixture was concentrated under reduced pressureproviding the product as a yellow oil. The oil was dissolved in EtOAc(50 mL) and passed through a silica gel plug (60-120 mesh) and the plugeluted with 10% MeOH in CHCl₃ to give the title compound as a colorlessliquid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.08 (d, J=2.4 Hz, 1H), 7.37 (d,J=8.7 Hz, 1H), 6.98 (dd, J=2.7 and 8.7 Hz, 1H), 3.78 (s, 3H), 2.26 (s,3H). MS (ESI, positive ion) m/z: 140.0 (M+H).

Step 3. 5-Methoxy-2-methyl-4-nitropyridine 1-oxide

To fuming nitric acid (20 mL, Spectrochem, India) was added(5-methoxy-2-methylpyridine 1-oxide (14 g, 0.100 mol) in one lot and thereaction was stirred at rt for 2 h. Reaction progress was monitored byTLC (50% EtOAc in pet ether.). After completion of the reaction, thereaction mixture was poured in to ice water (100 mL) and neutralizedwith 40% NaOH solution (PH ˜7-7.5) to get a yellow precipitate. Theprecipitate was stirred for 5-10 min, then filtered and dried to givethe title compound as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.51 (s, 1H), 8.21 (s, 1H), 3.95 (s, 3H), 2.31 (s, 3H). MS (ESI,positive ion) m/z: 184.8 (M+H).

Step 4. (5-Methoxy-4-nitropyridin-2-yl)methanol

5-Methoxy-2-methyl-4-nitropyridine 1-oxide (7 g, 0.038 mol) wasdissolved in acetic anhydride (70 mL, Sdfine, India) and the resultingsolution was stirred for 3 h at 150° C. The reaction mixture wasconcentrated and Et₂O (250 mL) was added to the residue and it wasneutralized with sat'd NaHCO₃ (100 mL). The organic layer was separatedand dried over anhydrous sodium sulfate, concentrated to afford a paleyellow solid which was dissolved in MeOH and THF (100 mL) and treatedwith LiOH (2.73 g, 0.113 mol). The reaction mixture was stirred for 2 hat rt. The progress of the reaction was monitored by TLC (5% MeOH inCHCl₃). After completion of acetate hydrolysis, sat NH₄Cl (20 mL) wasadded and the product was extracted with EtOAc. The organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure to afford the title compound as an off white solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.71 (s, 1H), 7.81 (s, 1H), 5.62 (t, J=5.7 Hz, 1H),4.59 (d, J=6 Hz, 2H), 4.04 (s, 3H). MS (ESI, positive ion) m/z: 185.1(M+H).

Step 5. 5-Methoxy-4-nitropicolinaldehyde

To a stirred solution of (5-methoxy-4-nitropyridin-2-yl)methanol (4 g,0.021 mol) in DCM (30 mL), was added Dess-Martin Periodinane (18.43 g,0.043 mol, Spectrochem, India) and reaction was stirred for 3 h at rt.The reaction progress was monitored by TLC (50% EtOAc in petroleumether). After completion of the reaction, sat'd NaHCO₃ (20 mL) was addedand the product was extracted with DCM (3×25 mL). The combined organiclayers were dried over anhydrous sodium sulfate and concentrated to givethe title compound as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δppm 9.95 (s, 1H), 9.02 (s, 1H), 8.36 (s, 1H), 4.19 (s, 3H). MS (ESI,positive ion) m/z: 182.9 (M+H).

Step 6. 5-Methoxy-4-nitropicolinic Acid

To a stirred solution of 5-methoxy-4-nitropicolinaldehyde (4 g, 0.02mol) in acetone and water (1:1, 100 mL) was added sodium chlorite (5.9g, 0.065 mol, spectrochem, india) and sulfamic acid (6.3 g, 0.065 mol,Rankem, India) and the reaction mixture was stirred for 1 h at rt.Reaction progress was monitored by TLC (50% EtOAc in petroleum ether).After completion, the reaction mixture was concentrated to get a whiteprecipitate which was filtered and dried to afford the title compound asa white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.6 (brs, 1H) 8.90 (s,1H), 8.41 (s, 1H), 4.15 (s, 3H). MS (ESI, positive ion) m/z: 197.8(M+H).

Step 7.(S)—N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-methoxy-4-nitropicolinamide

To a stirred solution of 5-methoxy-4-nitropicolinic acid (1 g, 0.005mol) in DMF (10 mL) were added(S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanaminehydrochloride (1.8 g, 0.0055 mol, Intermediate 6), HATU (2.8 g, 0.0075mol, molekula, India) and DIPEA (2.4 g, 0.02 mol, Aldrich). The reactionmixture was stirred for 12 h at rt. The reaction progress was monitoredby TLC (50% EtOAc in pet ether). After completion of reaction, water (10mL) was added and product was extracted with EtOAc (50 mL×3) andconcentrated to get initial product. The product thus obtained waspurified by column chromatography, silica gel (60-120 mesh), using80-100% EtOAc in petroleum ether as the eluent to give the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.74 (d, J=7.6 Hz, 1H), 8.94(s, 1H), 8.56 (d, J=4.8 Hz, 1H), 8.38 (s, 1H), 7.82 (t, J=8.8 Hz, 1H),7.57-7.53 (m, 3H), 7.35 (d, J=8.8 Hz, 1H), 6.55 (d, J=7.2 Hz, 1H), 4.16(s, 3H). MS (ESI, positive ion) m/z: 485.1 (M+H).

Step 8.(S)-4-Amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-methoxypicolinamide

To a stirred suspension of Raney Nickel (0.4 g, Monarch, India) in MeOH(10 mL) was added(S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-methoxy-4-nitropicolinamide(700 mg, 0.0014 mol) at rt. The reaction mixture was stirred under ahydrogen balloon for 2 h. After completion of the reaction, monitored byTLC (TLC eluent: 50% EtOAc in petroleum ether), the reaction mixture wasfiltered through Celite® brand filter agent and concentrated. Theresulting product was triturated with petroleum ether to give the titlecompound as a white solid. MS (ESI, positive ion) m/z: 455.2 (M+H).

Step 9.(S)-4-Amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-hydroxypicolinamide

To a stirred solution of(S)-4-amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-methoxypicolinamide (600 mg, 0.0013 mol)in NMP (10 mL) was added LiCl (168 mg, 0.0039 mol, Aldrich) followed bypTSA (754 mg, 0.0039 mol, Aldrich) at rt. The reaction mixture wasstirred at 180° C. for 2 h. After completion of the reaction (monitoredby TLC, 50% EtOAc in petroleum ether), the reaction mixture was cooledto room temperature and sat'd NaHCO₃ (50 mL) was added and the aqueoussolution was extracted with EtOAc (25 mL×2). The combined organic layerswere washed with water (25 mL×2), saturated NaCl (25 mL) and dried overanhydrous sodium sulfate. The product thus obtained was purified bysilica gel (60-120 mesh) column chromatography eluting with 60-70% EtOAcin petroleum ether to give the title compound as an off-white solid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 9.90 (s, 1H), 9.51 (d, J=8 Hz, 1H), 8.55(d, J=4.8 Hz, 1H), 7.82-7.78 (m, 2H), 7.56-7.50 (m, 2H), 7.46 (d, J=1.6Hz, 10.4 Hz, 1H), 7.30 (d, J=12.8, 2H), 6.48 (d, J=4.4 Hz, 1H), 5.78 (s,2H). MS (ESI, positive ion) m/z: 441.3 (M+H).

Step 10.(S)—N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-2-oxo-1,2-dihydrooxazolo[5,4-c]pyridine-6-carboxamide

To a cooled (−78° C.) stirred mixture of(S)-4-amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-hydroxypicolinamide(200 mg, 0.00045 mol) in THF (5 mL) were added TEA (0.31 mL, 0.002 mol,Spectrochem, India) and triphosgene (270 mg, 0.0009 mol, Spectrochem,India) in one lot and the reaction mixture was stirred for 2 h at thesame temperature, warmed to rt and stirred for 12 h. After completion ofthe reaction (monitored by TLC, 50% EtOAc in hexane), the reactionmixture was quenched with sat'd NaHCO₃ (5 mL), extracted with EtOAc (10mL×3). The organic layers were combined and dried over anhydrous sodiumsulfate and concentrated. The product thus obtained was purified bycolumn chromatography, silica gel (60-120 mesh) using 50-60% EtOAc inpetroleum ether as the eluent, and further purified using Prep TLCplates, mobile phase 50% EtOAc in hexanes to give the title compound. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 9.76 (d, J=7.6 Hz, 1H), 8.60 (s, 1H), 8.58(d, J=4.8 Hz, 1H), 7.82 (t, J=8.8 Hz, 1H), 7.70 (s, 1H), 7.56-7.50 (m,3H), 7.34 (d, J=8.4 Hz, 1H), 6.53 (d, J=6.8 Hz, 1H). MS (ESI, positiveion) m/z: 468.0 (M+H).

Example 438(S)—N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-2-oxo-2,3-dihydrooxazolo[4,5-c]pyridine-6-carboxamide

Step 1. 2-Methyl-4-nitropyridine 1-oxide

A 25 mL round bottom flask was charged with conc. H₂SO₄ (1 mL) andcooled to 0° C. 2-Methylpyridine 1-oxide (0.4 g, 0.003 mol, Aldrich) wasadded in one portion, followed by the addition of fuming HNO₃ (1 mL,spectrochem, india) in a drop-wise fashion. The reaction was stirred atrt for 30 min and a further 12 h at 70° C. Reaction progress wasmonitored by TLC (50% EtOAc in petroleum ether). After completion of thereaction, EtOAc (10 mL) was added to the reaction mixture after coolingto 0° C. and the reaction was neutralized to pH˜8-9 with 40% NaOHsolution, and extracted with EtOAc (2×10 mL). The combined organiclayers were dried over anhydrous sodium sulfate, filtered andconcentrated to give the title compound as a yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.82 (d, J=5.4 Hz, 1H), 8.03 (d, J=1.8 Hz, 1H), 7.92(dd, J=1.8, 5.1 Hz, 1H), 2.64 (s, 3H).

Step 2. 4-Methoxy-2-methylpyridine 1-oxide

To a stirred solution of 2-methyl-4-nitropyridine 1-oxide (24 g, 0.155mol) in MeOH (100 mL). Sodium methoxide (10 g, 0.187 mol, Aldrich) wasadded, and the reaction mixture was stirred for 2 h at 80° C. Reactionprogress was monitored by TLC (50% EtOAc in petroleum ether). Thereaction mixture was concentrated and water (50 mL) was added and theaqueous solution was extracted with EtOAc (4×50 mL). The combinedorganic layers were dried over sodium sulfate, filtered and concentratedto afford the title compound as a brown liquid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.14 (d, J=7.2 Hz, 1H), 7.14 (d, J=3.3 Hz, 1H), 6.91 (dd,J=3.6, 7.2 Hz, 1H), 3.80 (s, 3H), 2.32 (s, 3H).

Step 3. 4-Methoxy-2-methylpyridine

To a stirred solution of 4-methoxy-2-methylpyridine 1-oxide (20 g, 0.143mol) in AcOH (200 mL, sdfine, India), was added Fe (16 g, 0.287 mol,sdfine, India) and the reaction mixture was stirred for 2 h at 120° C.The reaction mixture was concentrated and neutralized with sat'd NaHCO₃.EtOAc was added to the mixture and it was filtered through Celite® brandfilter agent. The organic layer was separated and the aqueous layer wasextracted with EtOAc (3×150 mL). The combined organic layers were driedover sodium sulfate, filtered and concentrated to give the titlecompound as a brown liquid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.33 (d, J=6Hz, 1H), 6.68-6.64 (m, 2H), 3.84 (s, 3H), 2.52 (s, 3H). MS (ESI,positive ion) m/z: 124.0 (M+H).

Step 4. 4-Methoxy-2-methyl-5-nitropyridine

To a stirred solution of 4-methoxy-2-methylpyridine (25 g, 0.148 mol) inconc. H₂SO₄ (17 mL, S. D. Fine, India), a mixture of H₂SO₄ (17 mL, S.D.Fine, India) and 65% HNO₃ (22 mL, Rankem, India) was added in adrop-wise fashion at 0° C. over 30 min. The resulting solution washeated at 65° C. for 12 h. After completion, the reaction mixture waspoured in to ice water and neutralized (PH˜8) with 40% NaOH solution togive a yellow precipitate. The precipitate was further stirred andfiltered, dried to give a mixture of 3-nitro (major product) and thedesired 5-nitro isomers. The product was isolated by columnchromatography, silica gel (230-400), eluting with 15% EtOAc inpetroleum ether to give the title compound as yellow needles. ¹H NMR(400 MHz, DMSO-d₆) δ: 8.86 (s, 1H), 7.33 (s, 1H), 3.99 (s, 3H), 2.52 (s,3H). MS (ESI, positive ion) m/z: 169.0 (M+H).

Step 5. 4-Methoxy-5-nitropicolinic Acid

To a stirred solution of 4-methoxy-2-methyl-5-nitropyridine (2 g, 0.011mol) in 1,4-dioxane (20 mL), was added SeO₂ (3.2 g, 0.047 mol, Aldrich),and the reaction mixture was stirred for 12 h at 105° C. The progress ofreaction was monitored by TLC (30% EtOAc in hexane). After completion,the reaction mixture was cooled to rt and filtered. The filtrate wasconcentrated to afford the aldehyde intermediate which was dissolved inacetone and water (1:1, 5 mL) and treated with sodium chlorite (3.2 g,0.035 mol, Aldrich) and sulfamic acid (3.4 g, 0.035 mol, Aldrich). Thereaction mixture was stirred for 1 h at rt. The reaction progress wasmonitored by TLC (50% EtOAc in petroleum ether). After completion, thereaction mixture was concentrated to give a white precipitate, which wasfiltered and dried to afford the title compound as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 13.9 (br s, 1H), 9.06 (s, 1H), 7.92 (s, 1H),4.10 (s, 3H). MS (ESI, positive ion) m/z: 197.0 (M+H).

Step 6.(S)—N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-4-methoxy-5-nitropicolinamide

To a stirred solution of 4-methoxy-5-nitropicolinic acid (1 g, 0.005mol) in DMF (10 mL) were added(S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanaminehydrochloride (1.8 g, 0.0055 mol, Intermediate 6), HATU (2.8 g, 0.0075mol, Molicula, India) and DIPEA (2.4 g, 0.02 mol, Aldrich). The reactionmixture was stirred for 12 h at rt. The reaction progress was monitoredby TLC (50% EtOAc in petroleum ether). After completion of the reaction,water (100 mL) was added and aqueous solution was extracted with EtOAc(50 mL×3) and concentrated to give the product. The product thusobtained was purified by column chromatography, silica gel (60-120mesh), using 80-100% EtOAc in petroleum ether as the eluent to give thetitle compound. ¹H NMR (400 Mhz, DMSO-d₆) δ ppm 9.89 (d, J=7.2 Hz, 1H),9.13 (s, 1H), 8.57 (d, J=4.5 Hz, 1H), 7.92 (s, 1H), 7.82 (t, J=8.7 Hz,1H), 7.56 (t, J=4.8 Hz, 3H), 7.36 (d, J=8.4 Hz, 1H), 6.54 (d, J=6.3 Hz,1H), 4.11 (s, 3H). MS (ESI, positive ion) m/z: 485.0 (M+H).

Step 7.(S)—N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-4-hydroxy-5-nitropicolinamide

To a solution of 30% HBr in AcOH (10 mL, Spectrochem, India) was added(S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-4-methoxy-5-nitropicolinamide(1 g, 0.002 mol), and the resulting reaction mixture was stirred for 12h at 90° C. The reaction progress was monitored by TLC (50% EtOAc inpetroleum ether). After completion of the reaction, the reaction mixturewas concentrated and neutralized with sat'd NaHCO₃ solution (pH˜7-7.5)and the aqueous solution was extracted with EtOAc (3×10 mL). Thecombined organic layers were dried over anhydrous sodium sulfate, andconcentrated to afford the title compound as a pale yellow solid. ¹H NMR(DMSO-d₆) δ: 9.84 (d, J=7.5 Hz, 1H), 8.77 (s, 1H), 8.53 (d, J=4.5 Hz,1H), 7.83-7.70 (m, 1H), 7.57-7.49 (m, 3H), 7.38-7.31 (m, 2H), 6.56 (d,J=7.5 Hz, 1H). MS (ESI, positive ion) m/z: 471.4 (M+H).

Step 8.((S)-5-Amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-4-hydroxypicolinamide

To a stirred solution of(S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-4-hydroxy-5-nitropicolinamide(0.35 g, 0.0007 mol) in MeOH (10 mL) was added Raney Ni (0.3 g,Monarch), followed by hydrazine hydrate (2 mL, Aldrich) added in adrop-wise fashion at rt. The reaction mixture was stirred for 3 h. Aftercompletion of the reaction (monitored by TLC, 50% EtOAc in hexane), thereaction mixture was filtered through Celite® brand filter agent andconcentrated providing a residue. The residue was triturated with Et₂O,filtered dried under vacuum to give the title compound as a brown solid.¹H NMR (DMSO-d₆) δ: 9.41 (d, J=7.5 Hz, 1H), 8.55 (d, J=4.2 Hz, 1H),7.83-7.78 (m, 2H), 7.54-7.44 (m, 3H), 7.27 (d, J=9.9 Hz, 2H), 6.46 (d,J=6.9 Hz, 1H), 5.29 (s, 2H).

Step 9.(S)—N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-2-oxo-2,3-dihydrooxazolo[4,5-c]pyridine-6-carboxamide

To a cooled (−78° C.) and stirred mixture of((S)-5-amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-4-hydroxypicolinamide(200 mg, 0.00045 mol) in THF (5 mL) was added TEA (0.31 mL, 0.002 mol,Spectrochem, India) and triphosgene (270 mg, 0.0009 mol, Spectrochem,India). The reaction mixture was stirred for 2 h at same temperature,slowly warmed to rt and stirred overnight. After completion of thereaction (monitored by TLC, 50% EtOAc in hexane), the reaction mixturewas quenched with sat'd NaHCO₃ (5 mL), extracted with EtOAc (10 mL×3).The combined organic layers were dried over anhydrous sodium sulfate,concentrated and purified by column chromatography, silica gel (60-120mesh) using 50-60% EtOAc in petroleum ether as the eluent, followed byfurther purification using Prep TLC plates, mobile phase 50% EtOAc inhexanes to give the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.79(d, J=7.2 Hz, 1H), 9.00 (s, 1H), 8.53 (d, J=4.4 Hz, 1H), 8.41 (s, 1H),8.08 (s, 1H), 7.44-7.35 (m, 1H), 7.35-7.31 (m, 3H), 7.26-7.21 (m, 1H),6.64 (d, J=7.6 Hz, 1H). MS (ESI, positive ion) m/z: 467.2 (M+H).

TABLE 6 ¹H NMR Data of Examples 1-261 and 287-424. Freq., Ex. # Solvent¹HNMR Data (δ ppm) 1 400 MHz 8.38-8.52 (m, 1H), 8.14 (d, J = 2.2 Hz,1H), 8.04 (dd, J = 9.6, d₄-MeOH 2.5 Hz, 1H), 7.59 (ddd, J = 9.7, 8.5,1.2 Hz, 1H), 7.44-7.53 (m, J = 8.8 Hz, 2H), 7.41 (dt, J = 8.5, 4.4 Hz,1H), 7.15-7.26 (m, J = 8.0 Hz, 2H), 6.66 (s, 1H), 6.44-6.57 (m, 1H) 2400 MHz 8.97 (dd, J = 4.2, 1.5 Hz, 1H), 8.89 (d, J = 7.0 Hz, 1H), 8.62(s, CDCl₃ 1H), 8.45-8.52 (m, 1H), 8.25 (d, J = 8.2 Hz, 1H), 8.09 (dd, J= 8.5, 1.7 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.49-7.58 (m, 3H), 7.46(td, J = 8.6, 1.2 Hz, 1H), 7.28-7.39 (m, 1H), 7.17 (d, J = 8.6 Hz, 2H),6.68-6.75 (m, 1H) 3 400 MHz 8.92 (d, J = 4.1 Hz, 1H), 8.18 (dd, J = 8.0,1.0 Hz, 1H), 8.14 (d, d₄-MeOH J = 2.5 Hz, 1H), 8.03 (dd, J = 9.6, 2.7Hz, 1H), 7.58 (dd, J = 7.8, 4.9 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.45(d, J = 8.2 Hz, 1H), 7.29 (dd, J = 8.4, 2.2 Hz, 1H), 6.78 (s, 1H), 6.52(d, J = 9.6 Hz, 1H), 4.86 (br s, 2H) 4 400 MHz 9.06-9.11 (m, 1H),8.94-9.00 (m, 2H), 8.70 (d, J = 7.4 Hz, CDCl₃ 1H), 8.56 (s, 1H),8.12-8.20 (m, 2H), 8.02-8.10 (m, 2H), 7.97 (d, J = 9.0 Hz, 1H), 7.88 (d,J = 8.4 Hz, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.59 (dd, J = 9.0, 2.2 Hz,1H), 7.44-7.53 (m, 2H), 7.06 (d, J = 7.4 Hz, 1H) 5 400 MHz 8.97 (dd, J =4.2, 1.7 Hz, 1H), 8.87-8.92 (m, 1H), CDCl₃ 8.49-8.56 (m, 2H), 8.21 (dd,J = 8.2, 0.8 Hz, 1H), 8.08 (dd, J = 8.5, 1.7 Hz, 1H), 8.03 (dd, J = 8.2,0.6 Hz, 1H), 7.90 (d, J = 8.6 Hz, 1H), 7.43-7.52 (m, 2H), 7.21-7.26 (m,1H), 7.18 (dd, J = 12.2, 2.1 Hz, 1H), 6.90 (t, J = 8.6 Hz, 1H), 6.83 (d,J = 7.8 Hz, 1H) 6 400 MHz 8.91 (d, J = 2.2 Hz, 1H), 8.85 (d, J = 4.7 Hz,1H), 8.59 (d, J = 7.8 Hz, CDCl₃ 1H), 8.48 (s, 1H), 8.17 (d, J = 8.2 Hz,1H), 7.96-8.04 (m, 2H), 7.86 (d, J = 8.6 Hz, 1H), 7.40-7.50 (m, 2H),7.34-7.40 (m, 2H), 7.21-7.27 (m, 2H), 6.83 (d, J = 7.8 Hz, 1H) 7 400 MHz9.17 (s, 1H), 8.97 (dd, J = 9.7, 4.4 Hz, 2H), 8.71 (d, J = 7.2 Hz, CDCl₃1H), 8.56 (s, 1H), 8.33 (s, 1H), 8.19 (d, J = 8.2 Hz, 1H), 8.03-8.11 (m,2H), 7.89 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 7.4 Hz, 1H), 7.75 (d, J =8.2 Hz, 1H), 7.40-7.54 (m, 3H), 7.08 (d, J = 7.4 Hz, 1H) 8 400 MHz8.92-9.03 (m, 3H), 8.67 (d, J = 7.4 Hz, 1H), 8.56 (s, 1H), CDCl₃8.14-8.23 (m, 2H), 8.01-8.10 (m, 2H), 7.88 (d, J = 8.4 Hz, 1H), 7.67 (d,J = 9.0 Hz, 1H), 7.43-7.53 (m, 2H), 7.39 (br. s, 1H), 7.17 (dd, J = 9.0,2.0 Hz, 1H), 7.04 (d, J = 7.4 Hz, 1H), 3.92 (s, 3H) 9 400 MHz 9.19 (d, J= 1.8 Hz, 1H), 8.95-9.03 (m, 2H), 8.71 (d, J = 7.4 Hz, CDCl₃ 1H), 8.62(s, 1H), 8.58 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.04-8.12 (m, 2H),7.94-8.03 (m, 1H), 7.89 (d, J = 8.6 Hz, 1H), 7.59 (s, 1H), 7.57 (d, J =1.4 Hz, 1H), 7.44-7.54 (m, 2H), 7.12 (d, J = 7.6 Hz, 1H) 10 400 MHz8.90-8.97 (m, 2H), 8.72 (d, J = 7.4 Hz, 1H), 8.52 (s, 1H), d₄-MeOH 8.25(d, J = 8.2 Hz, 1H), 8.02-8.10 (m, 2H), 7.93 (d, J = 8.6 Hz, 1H),7.48-7.58 (m, 3H), 7.33-7.42 (m, 2H), 6.85 (d, J = 7.8 Hz, 1H) 11 400MHz 9.19 (s, 1H), 8.92 (d, J = 2.0 Hz, 1H), 8.87 (d, J = 4.7 Hz, 1H),CDCl₃ 8.33-8.43 (m, 2H), 8.18 (d, J = 1.4 Hz, 1H), 8.13 (d, J = 8.0 Hz,1H), 8.07 (d, J = 8.6 Hz, 1H), 7.98 (dd, J = 8.8, 1.4 Hz, 1H), 7.78-7.91(m, 3H), 7.60 (dd, J = 9.0, 2.3 Hz, 1H), 7.52 (dd, J = 7.7, 5.0 Hz, 1H),6.98-7.02 (m, 1H) 12 400 MHz 9.09 (d, J = 1.8 Hz, 1H), 8.92-9.00 (m,2H), 8.70 (d, J = 7.6 Hz, CDCl₃ 1H), 8.56 (s, 1H), 8.25 (s, 1H), 8.17(d, J = 8.2 Hz, 1H), 8.02-8.10 (m, 3H), 7.87 (d, J = 8.4 Hz, 1H), 7.79(d, J = 8.2 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.43-7.55 (m, 3H), 7.08(d, J = 7.6 Hz, 1H) 13 400 MHz 8.89-8.96 (m, 2H), 8.72 (d, J = 7.8 Hz,1H), 8.53 (s, 1H), CDCl₃ 8.26 (d, J = 8.2 Hz, 1H), 8.01-8.11 (m, 2H),7.93 (d, J = 8.4 Hz, 1H), 7.47-7.57 (m, 2H), 7.44 (s, 1H), 7.33-7.40 (m,1H), 7.21-7.28 (m, 2H), 6.89 (d, J = 7.8 Hz, 1H) 14 400 MHz 8.95 (dd, J= 4.2, 1.7 Hz, 1H), 8.87 (d, J = 4.1 Hz, 1H), 8.53 (s, CDCl₃ 1H), 8.44(d, J = 7.8 Hz, 1H), 8.16 (dd, J = 8.2, 0.8 Hz, 1H), 8.07 (dd, J = 8.5,1.7 Hz, 1H), 7.98 (dd, J = 8.0, 1.0 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H),7.44 (dd, J = 8.3, 4.2 Hz, 1H), 7.33-7.42 (m, 3H), 7.05-7.16 (m, 2H),6.89 (d, J = 7.8 Hz, 1H), 2.28 (s, 3H) 15 400 MHz 8.94-8.99 (m, J = 4.3,1.6 Hz, 1H), 8.92 (d, J = 4.7 Hz, 1H), CDCl₃ 8.61 (d, J = 7.8 Hz, 1H),8.56 (s, 1H), 8.17 (d, J = 8.2 Hz, 1H), 8.08 (dd, J = 8.5, 1.7 Hz, 1H),8.02 (d, J = 7.8 Hz, 1H), 7.74-7.90 (m, 5H), 7.65 (dd, J = 8.6, 1.4 Hz,1H), 7.38-7.49 (m, 4H), 7.09 (d, J = 8.0 Hz, 1H) 16 400 MHz 12.90 (br.s., 1H), 8.96-9.03 (m, 1H), 8.93 (d, J = 4.5 Hz, 1H), CDCl₃ 8.21 (d, J =7.6 Hz, 1H), 8.00-8.12 (m, 3H), 7.96 (d, J = 9.0 Hz, 1H), 7.88 (dd, J =9.6, 2.2 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.59 (dd, J = 9.0, 2.2 Hz,1H), 7.51 (dd, J = 7.7, 5.0 Hz, 1H), 6.92 (d, J = 7.4 Hz, 1H), 6.56 (d,J = 9.6 Hz, 1H) 17 400 MHz 8.97 (dd, J = 4.1, 1.4 Hz, 1H), 8.90 (d, J =4.5 Hz, 1H), 8.54 (s, CDCl₃ 1H), 8.47 (d, J = 7.8 Hz, 1H), 8.19 (d, J =8.0 Hz, 1H), 8.09 (dd, J = 8.5, 1.5 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H),7.89 (d, J = 8.6 Hz, 1H), 7.46 (td, J = 8.3, 4.6 Hz, 2H), 7.24-7.32 (m,2H), 7.16 (d, J = 9.8 Hz, 1H), 6.85-6.99 (m, 2H) 18 400 MHz 8.98 (dd, J= 4.2, 1.5 Hz, 1H), 8.92 (d, J = 4.5 Hz, 1H), CDCl₃ 8.50-8.58 (m, 2H),8.20 (d, J = 8.2 Hz, 1H), 8.09 (dd, J = 8.4, 1.6 Hz, 1H), 8.04 (d, J =7.8 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.69-7.78 (m, 2H), 7.39-7.55 (m,4H), 6.94 (d, J = 7.6 Hz, 1H) 19 400 MHz 8.93 (d, J = 3.3 Hz, 1H), 8.86(d, J = 4.3 Hz, 1H), 8.46-8.58 (m, CDCl₃ 2H), 8.13 (d, J = 8.2 Hz, 1H),8.06 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 8.6 Hz,1H), 7.34-7.48 (m, 4H), 6.79-6.92 (m, 3H), 3.73 (s, 3H) 20 400 MHz 9.12(d, J = 1.8 Hz, 1H), 8.95-9.00 (m, 2H), 8.71 (d, J = 7.4 Hz, CDCl₃ 1H),8.57 (s, 1H), 8.31 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 8.03-8.10 (m, 2H),7.89 (d, J = 8.6 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.40-7.55 (m, 3H),7.35 (ddd, J = 10.2, 7.7, 0.9 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H) 21 400MHz 8.96 (dd, J = 4.1, 1.2 Hz, 1H), 8.88 (d, J = 4.5 Hz, 1H), 8.54 (s,CDCl₃ 1H), 8.42 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 8.08 (dd,J = 8.4, 1.4 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 8.6 Hz,1H), 7.46 (dd, J = 8.3, 4.2 Hz, 1H), 7.40 (dd, J = 7.8, 4.9 Hz, 1H),7.30 (s, 1H), 7.24 (s, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 7.4Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 2.31 (s, 3H) 22 400 MHz 8.97 (dd, J =4.3, 1.6 Hz, 1H), 8.95 (d, J = 4.5 Hz, 1H), 8.87 (dd, CDCl₃ J = 4.1, 1.6Hz, 1H), 8.64 (d, J = 7.8 Hz, 1H), 8.56 (s, 1H), 8.18 (d, J = 8.2 Hz,1H), 8.13 (d, J = 7.6 Hz, 1H), 8.09 (dd, J = 8.6, 1.6 Hz, 1H), 8.05 (s,1H), 8.03 (s, 1H), 7.93 (s, 1H), 7.83-7.91 (m, 2H), 7.44-7.51 (m, 2H),7.37 (dd, J = 8.3, 4.2 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H) 23 400 MHz 9.05(d, J = 2.0 Hz, 1H), 8.97 (dd, J = 4.1, 1.6 Hz, 1H), 8.94 (d, d₄-MeOH J= 4.5 Hz, 1H), 8.68 (d, J = 7.6 Hz, 1H), 8.57 (s, 1H), 8.24 (d, J = 2.0Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 8.01-8.09 (m, 2H), 7.87 (d, J = 8.6Hz, 1H), 7.44-7.50 (m, 2H), 7.42 (d, J = 7.6 Hz, 1H), 7.36 (dd, J = 8.2,1.0 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 7.4 Hz, 1H), 4.03(s, 3H) 24 400 MHz 8.88-8.95 (m, 1H), 8.76-8.82 (m, 1H), 8.51 (br. s.,1H), CDCl₃ 8.11-8.25 (m, 2H), 7.94-8.09 (m, 2H), 7.87 (dd, J = 8.5, 2.8Hz, 1H), 7.44-7.51 (m, 1H), 7.38 (dt, J = 7.7, 3.7 Hz, 1H), 7.19-7.33(m, 3H), 6.85-6.94 (m, 2H), 3.82 (s, 3H) 25 400 MHz 8.97 (dd, J = 4.2,1.7 Hz, 1H), 8.89 (dd, J = 4.9, 0.8 Hz, 1H), CDCl₃ 8.53 (s, 1H), 8.47(d, J = 7.8 Hz, 1H), 8.18 (dd, J = 8.2, 0.8 Hz, 1H), 8.08 (dd, J = 8.5,1.7 Hz, 1H), 8.02 (dd, J = 7.8, 0.8 Hz, 1H), 7.88 (d, J = 8.6 Hz, 1H),7.41-7.49 (m, 2H), 7.21-7.26 (m, 1H), 7.19 (dd, J = 12.2, 2.1 Hz, 1H),6.89 (t, J = 8.6 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 3.83 (s, 3H) 26 400MHz 8.96 (dd, J = 4.1, 1.4 Hz, 1H), 8.88 (d, J = 4.3 Hz, 1H), 8.54 (s,CDCl₃ 1H), 8.50 (d, J = 7.8 Hz, 1H), 8.22 (d, J = 8.2 Hz, 1H), 8.08 (dd,J = 8.5, 1.3 Hz, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 8.4 Hz,1H), 7.49 (dd, J = 8.2, 4.3 Hz, 1H), 7.39-7.47 (m, 3H), 7.28-7.35 (m,2H), 6.89 (d, J = 7.8 Hz, 1H), 4.85 (q, J = 6.5 Hz, 1H), 2.47 (br. s.,1H), 1.44 (d, J = 6.5 Hz, 3H) 27 400 MHz 8.98 (d, J = 4.1 Hz, 1H), 8.89(d, J = 4.7 Hz, 1H), 8.45-8.56 (m, CDCl₃ 2H), 8.19 (d, J = 8.2 Hz, 1H),8.08 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 8.6 Hz,1H), 7.39-7.50 (m, 4H), 6.98 (t, J = 8.6 Hz, 2H), 6.88 (d, J = 7.8 Hz,1H) 28 400 MHz, 9.50 (d, J = 7.8 Hz, 1H), 9.01 (dd, J = 4.2, 1.7 Hz,1H), 8.61 (s, DMSO-d₆ 1H), 8.45 (d, J = 7.6 Hz, 1H), 8.23 (dd, J = 4.6,1.1 Hz, 1H), 8.00-8.12 (m, 2H), 7.59-7.77 (m, 5H), 7.47-7.56 (m, 1H),7.39 (dd, J = 8.4, 4.7 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 3.67 (s, 3H)29 400 MHz, 9.73 (d, J = 7.6 Hz, 1H), 9.04 (d, J = 4.5 Hz, 1H), 8.35(dd, J = 4.8, DMSO-d₆ 1.9 Hz, 1H), 8.29 (d, J = 7.6 Hz, 1H), 8.25 (dd, J= 7.4, 2.0 Hz, 1H), 7.66-7.77 (m, 3H), 7.57 (d, J = 8.2 Hz, 2H), 7.16(dd, J = 7.4, 4.9 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 4.06 (s, 3H) 30 400MHz, 9.37 (d, J = 7.4 Hz, 1H), 8.91 (d, J = 4.5 Hz, 1H), 8.71 (d, J =2.3 Hz, DMSO-d₆ 1H), 8.25 (d, J = 7.4 Hz, 1H), 8.18 (dd, J = 8.7, 2.4Hz, 1H), 7.66-7.76 (m, J = 8.2 Hz, 2H), 7.62 (dd, J = 7.9, 4.8 Hz, 1H),7.47-7.58 (m, J = 8.0 Hz, 2H), 6.86 (d, J = 8.6 Hz, 1H), 6.79 (d, J =7.4 Hz, 1H), 3.89 (s, 3H) 31 400 MHz, 9.84 (d, J = 8.2 Hz, 1H), 9.45(dd, J = 4.9, 1.6 Hz, 1H), 9.06 (d, DMSO-d₆ J = 4.3 Hz, 1H), 8.32 (d, J= 7.8 Hz, 1H), 8.24 (dd, J = 8.5, 1.7 Hz, 1H), 7.95 (dd, J = 8.4, 5.1Hz, 1H), 7.68-7.77 (m, 3H), 7.61 (d, J = 8.2 Hz, 2H), 6.80 (d, J = 8.2Hz, 1H) 32 400 MHz, 9.55 (d, J = 8.4 Hz, 1H), 9.04 (d, J = 4.3 Hz, 1H),8.49 (d, J = 5.9 Hz, DMSO-d₆ 1H), 8.30 (d, J = 7.8 Hz, 1H), 7.65-7.76(m, 3H), 7.48-7.60 (m, 3H), 7.20 (dd, J = 5.7, 2.7 Hz, 1H), 6.74 (d, J =8.6 Hz, 1H), 3.89 (s, 3H) 33 400 MHz, 9.54 (d, J = 8.4 Hz, 1H), 9.02 (d,J = 4.5 Hz, 1H), 8.31 (d, J = 7.6 Hz, DMSO-d₆ 1H), 7.90 (t, J = 7.8 Hz,1H), 7.67-7.75 (m, 3H), 7.65 (d, J = 7.2 Hz, 1H), 7.55 (d, J = 8.2 Hz,2H), 7.08 (d, J = 8.2 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 3.97 (s, 3H) 34400 MHz, 9.61 (d, J = 7.4 Hz, 1H), 8.91 (d, J = 4.7 Hz, 1H), 8.20-8.32(m, DMSO-d₆ 2H), 7.66-7.76 (m, J = 8.2 Hz, 2H), 7.63 (dd, J = 7.8, 4.9Hz, 1H), 7.47-7.56 (m, J = 8.2 Hz, 2H), 7.38 (d, J = 5.3 Hz, 1H), 7.25(s, 1H), 6.76 (d, J = 7.4 Hz, 1H), 3.87 (s, 3H) 35 400 MHz, 9.40 (d, J =7.8 Hz, 1H), 8.74 (d, J = 2.2 Hz, 1H), 8.45 (d, J = 4.7 Hz, DMSO-d₆ 1H),8.21 (dd, J = 8.7, 2.4 Hz, 1H), 7.74-7.80 (m, 1H), 7.72 (d, J = 8.2 Hz,2H), 7.63 (d, J = 8.2 Hz, 2H), 7.48 (dt, J = 8.5, 4.4 Hz, 1H), 6.89 (d,J = 8.8 Hz, 1H), 6.74 (d, J = 7.6 Hz, 1H), 3.91 (s, 3H) 36 400 MHz,10.00 (d, J = 6.8 Hz, 1H), 8.60 (d, J = 4.5 Hz, 1H), 8.39 (dd, J = 4.9,DMSO-d₆ 2.0 Hz, 1H), 8.27 (dd, J = 7.4, 2.0 Hz, 1H), 7.82 (td, J = 9.2,1.1 Hz, 1H), 7.68-7.77 (m, J = 8.2 Hz, 2H), 7.60-7.68 (m, J = 8.2 Hz,2H), 7.54 (dt, J = 8.5, 4.4 Hz, 1H), 7.19 (dd, J = 7.4, 4.9 Hz, 1H),6.60 (d, J = 5.9 Hz, 1H), 4.15 (s, 3H) 37 400 MHz, 9.64 (d, J = 8.2 Hz,1H), 9.05 (d, J = 4.3 Hz, 1H), 8.32 (d, J = 7.8 Hz, DMSO-d₆ 1H), 8.12(d, J = 9.2 Hz, 1H), 7.66-7.79 (m, 3H), 7.59 (d, J = 8.2 Hz, 2H), 7.40(d, J = 9.2 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 4.12 (s, 3H) 38 400 MHz,9.62 (d, J = 7.4 Hz, 1H), 8.94 (d, J = 4.1 Hz, 1H), 8.67 (d, J = 1.6 Hz,DMSO-d₆ 1H), 8.44 (d, J = 2.9 Hz, 1H), 8.24-8.33 (m, 1H), 7.78-7.87 (m,1H), 7.70-7.78 (m, J = 8.2 Hz, 2H), 7.65 (dd, J = 7.8, 4.9 Hz, 1H),7.50-7.59 (m, J = 8.2 Hz, 2H), 6.83 (d, J = 7.4 Hz, 1H), 3.88 (s, 3H) 39400 MHz, 9.58 (d, J = 6.7 Hz, 1H), 8.91 (d, J = 4.5 Hz, 1H), 8.55 (d, J= 5.1 Hz, DMSO-d₆ 1H), 8.26 (d, J = 7.8 Hz, 1H), 7.66-7.75 (m, 3H), 7.63(dd, J = 7.8, 4.9 Hz, 1H), 7.58 (d, J = 4.9 Hz, 1H), 7.53 (d, J = 8.2Hz, 2H), 6.78 (d, J = 6.5 Hz, 1H), 2.51 (s, 3H) 40 400 MHz, 9.49 (d, J =7.4 Hz, 1H), 8.87-8.97 (m, 2H), 8.26 (d, J = 7.2 Hz, DMSO-d₆ 1H), 8.14(dd, J = 8.2, 2.3 Hz, 1H), 7.67-7.75 (m, J = 8.2 Hz, 2H), 7.62 (dd, J =7.8, 4.9 Hz, 1H), 7.49-7.57 (m, J = 8.2 Hz, 2H), 7.33 (d, J = 8.0 Hz,1H), 6.80 (d, J = 7.2 Hz, 1H), 2.51 (s, 3H) 41 400 MHz, 9.12 (d, J = 7.4Hz, 1H), 8.92 (d, J = 3.9 Hz, 1H), 8.22-8.36 (m, DMSO-d₆ 1H), 8.17 (d, J= 2.5 Hz, 1H), 7.90 (dd, J = 9.7, 2.6 Hz, 1H), 7.68-7.75 (m, J = 8.2 Hz,2H), 7.63 (dd, J = 7.8, 4.9 Hz, 1H), 7.41-7.57 (m, J = 8.0 Hz, 2H), 6.76(d, J = 7.4 Hz, 1H), 6.33 (d, J = 9.6 Hz, 1H) 42 400 MHz, 9.62 (br. s.,1H), 9.06 (s, 2H), 8.94 (d, J = 4.1 Hz, 1H), DMSO-d₆ 8.22-8.33 (m, 1H),7.69-7.78 (m, J = 8.2 Hz, 2H), 7.65 (dd, J = 7.6, 4.9 Hz, 1H), 7.50-7.60(m, J = 8.2 Hz, 2H), 6.81 (br. s., 1H), 3.99 (s, 3H) 43 400 MHz, 12.14(br. s., 1H), 8.92 (d, J = 4.3 Hz, 1H), 8.84 (d, J = 8.0 Hz, DMSO-d₆1H), 8.46 (s, 1H), 8.39 (dd, J = 7.8, 1.6 Hz, 1H), 8.17-8.32 (m, 2H),7.66-7.75 (m, J = 8.4 Hz, 2H), 7.62 (dd, J = 7.9, 4.8 Hz, 1H), 7.46-7.58(m, J = 8.0 Hz, 2H), 7.15 (dd, J = 7.8, 4.7 Hz, 1H), 6.89 (d, J = 7.8Hz, 1H) 44 400 MHz, 11.76 (br. s., 1H), 9.50 (d, J = 7.2 Hz, 1H), 8.90(d, J = 4.5 Hz, DMSO-d₆ 1H), 8.25 (d, J = 7.4 Hz, 1H), 7.66-7.75 (m, J =8.2 Hz, 2H), 7.62 (dd, J = 7.9, 4.8 Hz, 1H), 7.46-7.55 (m, J = 8.2 Hz,2H), 7.42 (d, J = 6.8 Hz, 1H), 6.75-6.80 (m, 1H), 6.69 (d, J = 6.7 Hz,1H), 6.44 (dd, J = 6.8, 1.4 Hz, 1H) 45 400 MHz, 12.42 (br. s., 1H), 9.34(s, 1H), 9.09 (d, J = 7.8 Hz, 1H), 8.95 (d, DMSO-d₆ J = 4.3 Hz, 1H),8.76-8.88 (m, 1H), 8.47-8.62 (m, 1H), 8.29 (d, J = 7.8 Hz, 1H),7.69-7.78 (m, J = 8.0 Hz, 2H), 7.65 (dd, J = 7.8, 4.9 Hz, 1H), 7.50-7.60(m, J = 8.0 Hz, 2H), 6.91 (d, J = 7.8 Hz, 1H) 46 400 MHz, 9.41 (d, J =7.8 Hz, 1H), 8.76 (d, J = 2.3 Hz, 1H), 8.40-8.53 (m, DMSO-d₆ 1H), 8.22(dd, J = 8.8, 2.5 Hz, 1H), 7.76-7.82 (m, 1H), 7.74 (d, J = 8.4 Hz, 2H),7.65 (d, J = 8.2 Hz, 2H), 7.50 (dt, J = 8.5, 4.4 Hz, 1H), 6.90 (d, J =8.6 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 3.93 (s, 3H) 47 400 MHz, 10.01(d, J = 7.0 Hz, 1H), 8.60 (d, J = 4.7 Hz, 1H), 8.38 (dd, J = 4.9,DMSO-d₆ 2.0 Hz, 1H), 8.27 (dd, J = 7.4, 2.0 Hz, 1H), 7.82 (t, J = 8.9Hz, 1H), 7.69-7.77 (m, J = 8.2 Hz, 2H), 7.60-7.69 (m, J = 8.0 Hz, 2H),7.50-7.60 (m, 1H), 7.18 (dd, J = 7.6, 4.9 Hz, 1H), 6.60 (d, J = 6.3 Hz,1H), 4.15 (s, 3H) 48 400 MHz, 9.72 (d, J = 7.6 Hz, 1H), 9.02 (d, J = 4.5Hz, 1H), 8.59 (s, 1H), DMSO-d₆ 8.33 (d, J = 4.7 Hz, 1H), 8.29 (d, J =7.6 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.68 (dd, J = 8.1, 5.0 Hz, 1H),7.64 (d, J = 4.7 Hz, 1H), 7.57 (d, J = 8.2 Hz, 2H), 6.74 (d, J = 7.6 Hz,1H), 4.08 (s, 3H) 49 400 MHz, 9.52 (d, J = 7.0 Hz, 1H), 8.90 (d, J = 4.7Hz, 1H), 8.25 (d, J = 7.8 Hz, DMSO-d₆ 1H), 7.75 (d, J = 7.0 Hz, 1H),7.67-7.73 (m, J = 8.2 Hz, 2H), 7.62 (dd, J = 8.0, 4.9 Hz, 1H), 7.46-7.54(m, J = 8.0 Hz, 2H), 6.83-6.92 (m, 1H), 6.70 (d, J = 7.0 Hz, 1H), 6.50(dd, J = 7.0, 1.8 Hz, 1H), 3.43 (s, 3H) 50 400 MHz, 9.05 (d, J = 7.6 Hz,1H), 8.91 (d, J = 4.3 Hz, 1H), 8.50 (d, J = 2.5 Hz, DMSO-d₆ 1H), 8.25(d, J = 7.4 Hz, 1H), 7.88 (dd, J = 9.6, 2.5 Hz, 1H), 7.66-7.74 (m, J =8.4 Hz, 2H), 7.62 (dd, J = 7.9, 4.8 Hz, 1H), 7.46-7.55 (m, J = 8.2 Hz,2H), 6.76 (d, J = 7.6 Hz, 1H), 6.37 (d, J = 9.6 Hz, 1H), 3.45 (s, 3H) 51400 MHz, 12.01 (br. s., 1H), 9.15 (d, J = 7.8 Hz, 1H), 8.46 (d, J = 4.5Hz, DMSO-d₆ 1H), 8.19 (d, J = 2.5 Hz, 1H), 7.92 (dd, J = 9.7, 2.6 Hz,1H), 7.77 (td, J = 9.3, 1.0 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.61 (d,J = 8.0 Hz, 2H), 7.49 (dt, J = 8.5, 4.4 Hz, 1H), 6.71 (d, J = 7.8 Hz,1H), 6.35 (d, J = 9.8 Hz, 1H) 52 400 MHz, 9.54 (d, J = 7.6 Hz, 1H), 8.96(d, J = 2.0 Hz, 1H), 8.45 (d, J = 4.7 Hz, DMSO-d₆ 1H), 8.21 (dd, J =8.1, 2.2 Hz, 1H), 7.74-7.81 (m, 1H), 7.69-7.74 (m, J = 8.2 Hz, 2H),7.61-7.66 (m, J = 8.2 Hz, 2H), 7.48 (dt, J = 8.5, 4.3 Hz, 1H), 7.40 (d,J = 8.2 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 2.54 (s, 3H) 53 400 MHz, 9.69(d, J = 7.6 Hz, 1H), 8.64 (d, J = 5.3 Hz, 1H), 8.45 (d, J = 4.7 Hz,DMSO-d₆ 1H), 7.82 (s, 1H), 7.77 (t, J = 9.8 Hz, 1H), 7.68-7.75 (m, 3H),7.60-7.67 (m, 2H), 7.49 (dt, J = 8.5, 4.4 Hz, 1H), 6.73 (d, J = 7.6 Hz,1H), 2.57 (s, 3H) 54 400 MHz, 12.15 (br. s., 1H), 8.90 (d, J = 8.0 Hz,1H), 8.42-8.51 (m, 2H), DMSO-d₆ 8.40 (dd, J = 8.0, 1.6 Hz, 1H), 8.26(dd, J = 4.7, 1.6 Hz, 1H), 7.74-7.81 (m, 1H), 7.69-7.74 (m, J = 8.2 Hz,2H), 7.60-7.67 (m, J = 8.2 Hz, 2H), 7.48 (dt, J = 8.5, 4.3 Hz, 1H), 7.16(dd, J = 7.9, 4.6 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H) 55 400 MHz, 9.54 (d,J = 7.6 Hz, 1H), 9.02 (d, J = 4.3 Hz, 1H), 8.79 (s, 1H), DMSO-d₆ 8.56(d, J = 5.9 Hz, 1H), 8.29 (d, J = 7.2 Hz, 1H), 7.65-7.74 (m, 3H), 7.56(d, J = 8.2 Hz, 2H), 7.23 (d, J = 5.9 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H),4.03 (s, 3H) 56 400 MHz, 10.61 (br. s., 1H), 9.07 (d, J = 7.4 Hz, 1H),8.90 (d, J = 4.5 Hz, DMSO-d₆ 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.75-7.84(m, 2H), 7.66-7.73 (m, J = 8.2 Hz, 2H), 7.61 (dd, J = 7.9, 4.8 Hz, 1H),7.47-7.55 (m, J = 8.2 Hz, 2H), 6.83 (d, J = 8.0 Hz, 1H), 6.78 (d, J =7.4 Hz, 1H), 3.51 (s, 2H) 57 400 MHz, 9.74 (d, J = 5.9 Hz, 1H), 9.08 (s,2H), 8.92 (d, J = 4.3 Hz, 1H), DMSO-d₆ 8.27 (d, J = 8.0 Hz, 1H),7.68-7.76 (m, J = 8.2 Hz, 2H), 7.63 (dd, J = 7.8, 4.9 Hz, 1H), 7.50-7.60(m, J = 8.2 Hz, 2H), 6.80 (d, J = 5.5 Hz, 1H), 2.67 (s, 3H) 58 400 MHz,10.34 (br. s., 1H), 9.47 (d, J = 7.4 Hz, 1H), 8.90 (d, J = 4.5 Hz,DMSO-d₆ 1H), 8.48 (d, J = 1.8 Hz, 1H), 8.25 (d, J = 7.4 Hz, 1H), 8.22(d, J = 2.7 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.62 (dd, J = 7.8, 4.9Hz, 1H), 7.48-7.56 (m, 3H), 6.77 (d, J = 7.4 Hz, 1H) 59 400 MHz, 12.46(br. s., 1H), 11.21 (d, J = 8.2 Hz, 1H), 8.96 (d, J = 4.5 Hz, DMSO-d₆1H), 8.32 (dd, J = 7.2, 2.2 Hz, 1H), 8.26 (d, J = 7.4 Hz, 1H), 7.66-7.78(m, 3H), 7.64 (dd, J = 7.8, 4.9 Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H), 6.80(d, J = 8.2 Hz, 1H), 6.47 (t, J = 6.7 Hz, 1H) 60 400 MHz, 9.77 (d, J =6.7 Hz, 1H), 9.07 (s, 1H), 8.92 (d, J = 4.1 Hz, 1H), DMSO-d₆ 8.69 (s,1H), 8.22-8.32 (m, 1H), 7.69-7.78 (m, J = 8.2 Hz, 2H), 7.63 (dd, J =7.8, 4.9 Hz, 1H), 7.55-7.61 (m, J = 8.2 Hz, 2H), 6.74 (d, J = 6.3 Hz,1H), 2.43 (s, 3H) 61 400 MHz, 10.88 (d, J = 8.0 Hz, 1H), 9.00 (d, J =4.3 Hz, 1H), 8.63 (s, 1H), DMSO-d₆ 8.39-8.48 (m, 1H), 8.29 (d, J = 7.0Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.67 (dd, J = 7.9, 5.0 Hz, 1H), 7.55(d, J = 8.0 Hz, 2H), 6.81 (d, J = 8.0 Hz, 1H) 62 400 MHz, 11.27 (br. s.,1H), 9.52 (d, J = 8.4 Hz, 1H), 9.04 (d, J = 4.5 Hz, DMSO-d₆ 1H),8.21-8.41 (m, 2H), 7.64-7.79 (m, 3H), 7.53 (d, J = 8.2 Hz, 2H), 7.41 (d,J = 2.2 Hz, 1H), 6.92 (d, J = 3.7 Hz, 1H), 6.71 (d, J = 8.6 Hz, 1H) 63400 MHz, 11.39 (br. s., 1H), 9.26 (d, J = 8.0 Hz, 1H), 9.00 (d, J = 4.5Hz, DMSO-d₆ 1H), 8.30 (d, J = 8.0 Hz, 1H), 7.62-7.84 (m, 4H), 7.51 (d, J= 8.0 Hz, 2H), 7.44 (d, J = 6.3 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.75(d, J = 8.2 Hz, 1H) 64 400 MHz, 11.39 (br. s., 1H), 9.26 (d, J = 8.6 Hz,1H), 9.03 (d, J = 4.5 Hz, DMSO-d₆ 1H), 8.29 (d, J = 7.8 Hz, 1H), 8.16(d, J = 2.5 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.64-7.77 (m, 3H), 7.53(d, J = 8.0 Hz, 2H), 7.29 (dd, J = 8.6, 2.7 Hz, 1H), 6.73 (d, J = 8.6Hz, 1H) 65 400 MHz, 9.06 (dd, J = 7.4, 5.9 Hz, 1H), 8.89 (d, J = 4.5 Hz,1H), 8.24 (d, DMSO-d₆ J = 8.0 Hz, 1H), 7.69 (d, J = 7.6 Hz, 2H), 7.61(dd, J = 7.8, 4.9 Hz, 1H), 7.34-7.51 (m, 3H), 6.57 (d, J = 7.0 Hz, 1H),3.20-3.27 (m, 1H), 2.72-2.86 (m, 1H), 2.03-2.24 (m, 2H), 1.85-2.00 (m,1H), 1.64-1.85 (m, 2H) 66 400 MHz, 12.19 (br. s., 1H), 9.34 (d, J = 7.4Hz, 1H), 8.94 (d, J = 4.5 Hz, DMSO-d₆ 1H), 8.33 (d, J = 3.5 Hz, 1H),8.27 (d, J = 7.6 Hz, 1H), 8.05 (d, J = 7.0 Hz, 1H), 7.68-7.78 (m, J =8.2 Hz, 2H), 7.64 (dd, J = 7.8, 4.9 Hz, 1H), 7.52-7.59 (m, J = 8.2 Hz,2H), 7.28 (s, 1H), 7.10 (dd, J = 7.8, 4.7 Hz, 1H), 6.84 (d, J = 7.0 Hz,1H) 67 400 MHz, 11.89 (br. s., 1H), 9.33 (d, J = 7.4 Hz, 1H), 8.92 (d, J= 4.5 Hz, DMSO-d₆ 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.52 (d, J = 2.2 Hz,1H), 8.26 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.62 (dd, J =7.8, 4.9 Hz, 1H), 7.51-7.59 (m, 3H), 6.84 (d, J = 7.4 Hz, 1H), 6.54 (d,J = 3.5 Hz, 1H) 68 400 MHz, 9.08 (d, J = 7.8 Hz, 1H), 8.51 (d, J = 2.5Hz, 1H), 8.45 (d, J = 4.7 Hz, DMSO-d₆ 1H), 7.90 (dd, J = 9.5, 2.6 Hz,1H), 7.68-7.82 (m, 3H), 7.60 (d, J = 8.2 Hz, 2H), 7.47 (dt, J = 8.5, 4.4Hz, 1H), 6.70 (d, J = 7.8 Hz, 1H), 6.39 (d, J = 9.4 Hz, 1H), 3.47 (s,3H) 69 400 MHz, 10.49 (s, 1H), 9.27 (d, J = 7.4 Hz, 1H), 8.90 (d, J =4.7 Hz, 1H), DMSO-d₆ 8.25 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 8.2 Hz, 2H),7.62 (dd, J = 8.0, 4.9 Hz, 1H), 7.45-7.56 (m, 3H), 7.21-7.33 (m, 2H),6.78 (d, J = 7.4 Hz, 1H), 3.52 (s, 2H) 70 400 MHz, 10.62 (s, 1H), 9.13(d, J = 7.8 Hz, 1H), 8.44 (d, J = 4.7 Hz, 1H), DMSO-d₆ 7.79-7.85 (m,2H), 7.75 (t, J = 9.3 Hz, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.62 (d, J =8.2 Hz, 2H), 7.47 (dt, J = 8.5, 4.4 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H),6.71 (d, J = 7.6 Hz, 1H), 3.53 (s, 2H) 71 400 MHz, 10.50 (s, 1H), 9.31(d, J = 7.6 Hz, 1H), 8.45 (d, J = 4.7 Hz, 1H), DMSO-d₆ 7.76 (t, J = 9.3Hz, 1H), 7.68-7.73 (m, J = 8.4 Hz, 2H), 7.59-7.65 (m, J = 8.2 Hz, 2H),7.51-7.56 (m, 1H), 7.45-7.51 (m, 1H), 7.32 (s, 1H), 7.28 (d, J = 7.8 Hz,1H), 6.71 (d, J = 7.6 Hz, 1H), 3.53 (s, 2H) 72 400 MHz, 12.50 (br. s.,1H), 11.32 (d, J = 7.8 Hz, 1H), 8.47-8.55 (m, 1H), DMSO-d₆ 8.34 (dd, J =7.2, 2.2 Hz, 1H), 7.69-7.85 (m, 4H), 7.59 (d, J = 8.0 Hz, 2H), 7.50 (dt,J = 8.5, 4.4 Hz, 1H), 6.69 (d, J = 7.4 Hz, 1H), 6.50 (dd, J = 7.0, 6.5Hz, 1H) 73 400 MHz, 10.92 (s, 1H), 9.21 (d, J = 7.6 Hz, 1H), 8.44 (d, J= 4.7 Hz, 1H), DMSO-d₆ 7.72-7.79 (m, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.61(d, J = 8.2 Hz, 2H), 7.53-7.59 (m, 2H), 7.47 (dt, J = 8.5, 4.3 Hz, 1H),6.93 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 7.6 Hz, 1H), 4.61 (s, 2H) 74 400MHz, 9.60 (d, J = 7.8 Hz, 1H), 8.45 (d, J = 4.7 Hz, 1H), 8.05-8.15 (m,DMSO-d₆ J = 8.4 Hz, 2H), 7.82-7.89 (m, J = 8.4 Hz, 2H), 7.74-7.81 (m,1H), 7.69-7.74 (m, J = 8.2 Hz, 2H), 7.61-7.68 (m, J = 8.2 Hz, 2H), 7.58(d, J = 5.1 Hz, 1H), 7.44-7.52 (m, 1H), 6.74 (d, J = 7.6 Hz, 1H), 2.42(d, J = 5.1 Hz, 3H) 75 400 MHz, 10.81 (s, 1H), 9.22 (d, J = 7.6 Hz, 1H),8.44 (d, J = 4.7 Hz, 1H), DMSO-d₆ 7.73-7.79 (m, 1H), 7.68-7.73 (m, J =8.2 Hz, 2H), 7.59-7.65 (m, J = 8.2 Hz, 2H), 7.57 (dd, J = 8.4, 2.0 Hz,1H), 7.47 (dt, J = 8.5, 4.4 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.00 (d,J = 8.4 Hz, 1H), 6.69 (d, J = 7.6 Hz, 1H), 4.63 (s, 2H) 76 400 MHz,11.84 (br. s., 1H), 9.37 (d, J = 7.6 Hz, 1H), 8.45 (d, J = 4.5 Hz,DMSO-d₆ 1H), 7.73-7.80 (m, 1H), 7.71 (d, J = 8.2 Hz, 3H), 7.59-7.66 (m,3H), 7.47 (dt, J = 8.5, 4.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.73 (d,J = 7.6 Hz, 1H) 77 400 MHz, 10.89 (s, 1H), 9.79 (d, J = 7.2 Hz, 1H),8.57 (d, J = 4.7 Hz, 1H), DMSO-d₆ 7.75-7.82 (m, 1H), 7.68-7.74 (m, J =8.4 Hz, 2H), 7.59-7.65 (m, J = 8.2 Hz, 2H), 7.51 (dt, J = 8.6, 4.4 Hz,1H), 7.43 (dd, J = 6.7, 2.8 Hz, 1H), 7.00-7.11 (m, 2H), 6.58 (d, J = 6.7Hz, 1H), 4.75-4.99 (m, 2H) 78 400 MHz, 9.28 (d, J = 7.8 Hz, 1H), 8.45(d, J = 4.5 Hz, 1H), 7.87 (s, 1H), DMSO-d₆ 7.78 (t, J = 9.4 Hz, 2H),7.69-7.74 (m, 3H), 7.59-7.67 (m, 2H), 7.43-7.53 (m, 1H), 7.13 (d, J =8.0 Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H) 79 400 MHz, 11.86 (br. s., 1H),9.34 (d, J = 7.6 Hz, 1H), 8.46 (d, J = 4.7 Hz, DMSO-d₆ 1H), 7.68-7.82(m, 2H), 7.65 (s, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.47 (dt, J = 8.5, 4.3Hz, 1H), 7.35 (d, J = 8.2 Hz, 3H), 6.68 (d, J = 7.6 Hz, 1H) 80 400 MHz,11.87 (br. s., 1H), 9.24 (d, J = 7.8 Hz, 1H), 8.37-8.52 (m, 1H), DMSO-d₆7.89 (d, J = 1.4 Hz, 1H), 7.81 (dd, J = 8.2, 1.6 Hz, 1H), 7.76 (ddd, J =10.0, 8.6, 1.2 Hz, 1H), 7.51-7.59 (m, J = 8.6 Hz, 2H), 7.44-7.51 (m,1H), 7.31-7.40 (m, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 1H), 6.70 (d, J= 7.6 Hz, 1H) 81 400 MHz, 10.92 (br. s., 1H), 9.15 (d, J = 7.6 Hz, 1H),8.44 (d, J = 4.5 Hz, DMSO-d₆ 1H), 7.74 (t, J = 9.3 Hz, 1H), 7.54-7.59(m, 2H), 7.48-7.54 (m, J = 8.6 Hz, 2H), 7.46 (dt, J = 8.5, 4.3 Hz, 1H),7.26-7.39 (m, J = 8.4 Hz, 2H), 6.93 (d, J = 8.6 Hz, 1H), 6.65 (d, J =7.8 Hz, 1H), 4.61 (s, 2H) 82 400 MHz, 11.98 (br. s., 1H), 9.07 (d, J =7.4 Hz, 1H), 8.46 (d, J = 4.3 Hz, DMSO-d₆ 1H), 8.15 (d, J = 2.3 Hz, 1H),7.90 (dd, J = 9.7, 2.6 Hz, 1H), 7.76 (d, J = 7.4 Hz, 1H), 7.65-7.73 (m,J = 8.2 Hz, 2H), 7.53-7.60 (m, J = 8.2 Hz, 2H), 7.37 (dd, J = 7.4, 5.1Hz, 1H), 6.59 (d, J = 7.4 Hz, 1H), 6.33 (d, J = 9.6 Hz, 1H), 2.24-2.40(m, 3H) 83 400 MHz, 9.01 (d, J = 7.4 Hz, 1H), 8.41-8.57 (m, 2H), 7.90(dd, J = 9.5, DMSO-d₆ 2.6 Hz, 1H), 7.77 (d, J = 7.4 Hz, 1H), 7.66-7.75(m, J = 8.2 Hz, 2H), 7.54-7.63 (m, J = 8.2 Hz, 2H), 7.38 (dd, J = 7.3,5.0 Hz, 1H), 6.62 (d, J = 7.4 Hz, 1H), 6.39 (d, J = 9.6 Hz, 1H), 3.46(s, 3H), 2.35 (s, 3H) 84 400 MHz, 11.82 (br. s., 1H), 9.27 (d, J = 7.8Hz, 1H), 8.43 (d, J = 3.9 Hz, DMSO-d₆ 1H), 7.68 (d, J = 8.4 Hz, 3H),7.65 (d, J = 7.6 Hz, 1H), 7.56-7.62 (m, 3H), 7.33 (d, J = 8.4 Hz, 1H),7.28 (dd, J = 7.6, 4.7 Hz, 1H), 6.47-6.69 (m, 1H), 2.22-2.41 (m, 3H) 85400 MHz, 10.92 (br. s., 1H), 9.12 (d, J = 7.6 Hz, 1H), 8.43 (d, J = 4.3Hz, DMSO-d₆ 1H), 7.68 (d, J = 8.2 Hz, 2H), 7.64 (d, J = 7.4 Hz, 1H),7.50-7.60 (m, 4H), 7.27 (dd, J = 7.5, 4.8 Hz, 1H), 6.93 (d, J = 8.2 Hz,1H), 6.58 (d, J = 7.6 Hz, 1H), 4.61 (s, 2H), 2.32 (s, 3H) 86 400 MHz9.58 (d, J = 7.6 Hz, 1 H), 8.59-8.65 (m, 1 H), 8.45-8.51 (m, 1 DMSO-d₆H), 8.32 (s, 1 H), 8.09 (s, 1 H), 7.72-7.83 (m, 4 H), 7.66-7.70 (m, 2H), 7.50 (dt, J = 8.5, 4.4 Hz, 1H), 7.37 (dd, J = 7.1, 1.7 Hz, 1H), 6.77(d, J = 7.6 Hz, 1H) 87 400 MHz 9.52 (d, J = 7.8 Hz, 1 H), 8.62 (d, J =7.0 Hz, 1 H), 8.48 (d, J = 4.5 Hz, DMSO-d6 1 H), 8.31 (s, 1 H), 8.08 (s,1 H), 7.72-7.82 (m, 2 H), 7.58 (d, J = 8.6 Hz, 2 H), 7.49 (dt, J = 8.5,4.3 Hz, 1 H), 7.37 (td, J = 4.8, 2.5 Hz, 3 H), 6.71 (d, J = 7.6 Hz, 1 H)88 400 MHz 9.52 (d, J = 7.8 Hz, 1 H), 8.62 (d, J = 7.0 Hz, 1 H), 8.48(d, J = 4.5 Hz, DMSO-d₆ 1 H), 8.31 (s, 1 H), 8.08 (s, 1 H), 7.72-7.82(m, 2 H), 7.58 (d, J = 8.6 Hz, 2 H), 7.49 (dt, J = 8.5, 4.3 Hz, 1 H),7.37 (td, J = 4.8, 2.5 Hz, 3 H), 6.71 (d, J = 7.6 Hz, 1 H) 89 300 MHz9.23 (s, 1H), 9.02 (d, J = 6.7 Hz, 1H), 8.54 (d, J = 4.5 Hz, 1H), CDCl₃8.14-8.33 (m, 2H), 7.94 (s, 2H), 7.56-7.70 (m, 1H), 7.37-7.54 (m, 3H),7.17 (d, J = 8.2 Hz, 2H), 6.70 (d, J = 6.3 Hz, 1H) 90 300 MHz 10.50 (s,1H), 9.25 (d, J = 7.7 Hz, 1H), 8.46 (d, J = 4.7 Hz, 1H), DMSO-d₆ 7.75(ddd, J = 10.0, 8.5, 1.2 Hz, 1H), 7.42-7.64 (m, 4H), 7.20-7.39 (m, 4H),6.66 (d, J = 6.9 Hz, 1H), 3.54 (s, 2H) 91 300 MHz 8.63 (br. s., 4H),8.49 (d, J = 4.7 Hz, 5H), 8.39 (d, J = 7.2 Hz, CDCl₃ 4H), 7.67-7.89 (m,2H), 7.42-7.55 (m, 3H), 7.30-7.41 (m, 1H), 7.15 (d, J = 8.0 Hz, 2H),6.94 (d, J = 8.0 Hz, 1H), 6.68 (dd, J = 7.1, 1.7 Hz, 1H), 3.60 (s, 2H)92 400 MHz 13.23 (br. s., 1H), 8.54 (dd, J = 4.9, 1.6 Hz, 1H), 8.43 (d,J = 6.8 Hz, CDCl₃ 1H), 8.11 (d, J = 2.5 Hz, 1H), 7.95 (dd, J = 9.6, 2.5Hz, 1H), 7.69 (dd, J = 7.8, 1.6 Hz, 1H), 7.48-7.60 (m, 4H), 7.23 (dd, J= 7.8, 4.9 Hz, 1H), 6.69 (d, J = 6.8 Hz, 1H), 6.61 (d, J = 9.4 Hz, 1H),2.11 (s, 3H) 93 400 MHz 8.99 (dd, J = 4.3, 1.6 Hz, 1H), 8.76 (d, J = 6.8Hz, 1H), 8.58 (dd, DMSO-d₆ J = 4.9, 1.6 Hz, 1H), 8.41 (s, 1H), 8.28 (dd,J = 8.2, 1.6 Hz, 1H), 8.18 (s, 2H), 7.72 (dd, J = 7.8, 1.6 Hz, 1H),7.60-7.68 (m, J = 8.0 Hz, 2H), 7.52-7.59 (m, J = 8.4 Hz, 2H), 7.47 (dd,J = 8.2, 4.3 Hz, 1H), 7.18-7.25 (m, 1H), 6.83 (d, J = 6.8 Hz, 1H), 2.15(s, 3H) 94 300 MHz 8.94 (d, J = 4.4 Hz, 1H), 8.48 (d, J = 7.6 Hz, 1H),8.22-8.36 (m, CDCl₃ 2H), 8.16 (br. s., 1H), 8.08 (d, J = 7.7 Hz, 1H),7.94 (d, J = 7.7 Hz, 1H), 7.39-7.73 (m, 5H), 6.88 (d, J = 7.6 Hz, 1H) 95300 MHz 8.60-8.92 (m, 2H), 8.03 (dd, J = 8.0, 1.2 Hz, 1H), 7.91 (d, J =8.9 Hz, CDCl₃ 2H), 7.42-7.68 (m, 5H), 7.08 (d, J = 7.7 Hz, 1H), 6.93 (d,J = 8.8 Hz, 2H), 3.85 (s, 3H), 2.17 (s, 3H) 96 400 MHz 8.73 (d, J = 2.3Hz, 1H), 8.53 (dd, J = 4.8, 1.5 Hz, 2H), CDCl₃ 8.06 (dd, J = 8.7, 2.4Hz, 1H), 7.69 (dd, J = 7.8, 1.6 Hz, 1H), 7.44-7.63 (m, 4H), 7.22 (dd, J= 7.8, 4.9 Hz, 1H), 6.46-6.85 (m, 2H), 3.91-4.01 (m, 3H), 2.13 (s, 3H)97 400 MHz 9.18-9.50 (m, 2H), 9.11 (br. s., 1H), 8.60-8.90 (m, 2H),CDCl₃ 8.38 (d, J = 8.4 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.86-8.08 (m,2H), 7.37-7.80 (m, 5H), 7.02 (d, J = 6.5 Hz, 1H), 2.18 (s, 3H) 98 300MHz 8.49-8.69 (m, 2H), 7.83-8.06 (m, 2H), 7.76 (dd, J = 7.9, 1.6 Hz,CDCl₃ 1H), 7.37-7.66 (m, 7H), 7.26-7.32 (m, 1H), 6.86 (d, J = 7.2 Hz,1H), 2.14 (s, 3H) 99 400 MHz 8.97 (d, J = 3.5 Hz, 1H), 8.65 (d, J = 3.5Hz, 1H), 8.31-8.49 (m, d₄-MeOH 2H), 8.24 (d, J = 7.6 Hz, 1H), 8.09 (d, J= 7.0 Hz, 2H), 7.32-7.92 (m, 7H), 6.98 (br. s., 1H) 100 400 MHz 8.93 (d,J = 4.7 Hz, 1H), 8.29 (d, J = 7.8 Hz, 1H), 8.01-8.16 (m, CDCl₃ 2H), 7.95(d, J = 8.2 Hz, 1H), 7.81 (dd, J = 8.1, 1.7 Hz, 1H), 7.39-7.65 (m, 5H),6.87 (d, J = 7.8 Hz, 1H) 101 300 MHz 9.33 (d, J = 4.2 Hz, 1H), 9.20 (d,J = 7.3 Hz, 1H), 8.88 (d, J = 8.3 Hz, CDCl₃ 1H), 8.65-8.79 (m, 2H),8.43-8.65 (m, 2H), 8.05 (dd, J = 7.9, 1.3 Hz, 1H), 7.95 (dd, J = 8.3,5.1 Hz, 1H), 7.40-7.69 (m, 5H), 7.06 (d, J = 7.3 Hz, 1H), 4.91 (dd, J =10.4, 5.6 Hz, 2H), 4.56 (dd, J = 5.6, 2.6 Hz, 2H), 1.75 (s, 3H) 102 300MHz 8.48 (d, J = 4.5 Hz, 1H), 8.14 (d, J = 2.2 Hz, 1H), 8.04 (dd, J =9.6, d₄-MeOH 2.6 Hz, 1H), 7.63 (td, J = 9.1, 1.3 Hz, 1H), 7.34-7.51 (m,3H), 7.26-7.34 (m, 1H), 6.65 (s, 1H), 6.53 (d, J = 9.6 Hz, 1H) 103 300MHz 8.50 (d, J = 4.7 Hz, 1H), 8.42 (d, J = 2.6 Hz, 1H), 8.00 (dd, J =9.4, d₄-MeOH 2.6 Hz, 1H), 7.65 (td, J = 9.1, 1.2 Hz, 1H), 7.27-7.52 (m,4H), 6.67 (s, 1H), 6.56 (d, J = 9.5 Hz, 1H), 3.63 (s, 3H) 104 300 MHz8.70 (d, J = 2.8 Hz, 1H), 8.51 (d, J = 4.7 Hz, 1H), 8.43 (s, 1H),d₄-MeOH 7.99-8.11 (m, 2H), 7.85 (d, J = 2.6 Hz, 1H), 7.59-7.71 (m, 5H),7.46 (dt, J = 8.4, 4.3 Hz, 1H), 6.81 (s, 1H) 105 300 MHz 8.50 (d, J =4.8 Hz, 1H), 8.01 (d, J = 9.5 Hz, 1H), 7.85 (s, 1H), d₄-MeOH 7.69-7.82(m, 2H), 7.58-7.69 (m, 5H), 7.46 (dt, J = 8.4, 4.3 Hz, 1H), 6.76 (s,1H), 6.70 (d, J = 9.5 Hz, 1H) 106 300 MHz 8.93 (d, J = 4.2 Hz, 1H), 8.21(d, J = 6.9 Hz, 1H), 8.00 (d, J = 9.5 Hz, d₄-MeOH 1H), 7.80 (s, 1H),7.72-7.78 (m, 1H), 7.51-7.71 (m, 6H), 6.93 (s, 1H), 6.69 (d, J = 9.6 Hz,1H) 107 300 MHz 8.91 (d, J = 4.8 Hz, 1H), 8.15-8.27 (m, 1H), 7.81-7.90(m, d₄-MeOH 2H), 7.64-7.70 (m, 1H), 7.51-7.64 (m, 2H), 7.41-7.51 (m,2H), 7.31-7.41 (m, 2H), 6.90 (s, 1H) 108 300 MHz 8.89-9.01 (m, 3H), 8.60(d, J = 1.8 Hz, 1H), 8.13-8.31 (m, 3H), d₄-MeOH 7.55-7.73 (m, 2H),7.36-7.48 (m, 2H), 6.96 (s, 1H) 109 300 MHz 8.94 (d, J = 4.4 Hz, 1H),8.82 (d, J = 1.9 Hz, 1H), 8.13-8.32 (m, d₄-MeOH 3H), 7.75 (d, J = 8.8Hz, 1H), 7.53-7.70 (m, 5H), 6.96 (s, 1H), 6.59 (d, J = 7.3 Hz, 1H) 110300 MHz 8.94 (d, J = 4.7 Hz, 1H), 8.90 (d, J = 2.5 Hz, 1H), 8.54 (s,1H), d₄-MeOH 8.48 (d, J = 1.9 Hz, 1H), 8.21 (d, J = 8.0 Hz, 1H),7.96-8.10 (m, 2H), 7.55-7.69 (m, 5H), 6.98 (s, 1H) 111 300 MHz 9.26 (d,J = 1.2 Hz, 1H), 8.98 (d, J = 4.2 Hz, 1H), 8.81 (d, J = 2.5 Hz, d₄-MeOH1H), 8.65-8.75 (m, 1H), 8.23 (d, J = 7.9 Hz, 1H), 7.58-7.71 (m, 2H),7.30-7.45 (m, 2H), 6.86 (s, 1H) 112 300 MHz 8.98 (d, J = 4.1 Hz, 1H),8.59-8.71 (m, 1H), 8.18-8.28 (m, d₄-MeOH 1H), 8.11 (dt, J = 7.9, 1.0 Hz,1H), 7.97 (td, J = 7.7, 1.7 Hz, 1H), 7.53-7.70 (m, 3H), 7.32-7.45 (m,2H), 6.84 (s, 1H) 113 300 MHz 8.86-8.92 (m, 2H), 8.51 (d, J = 4.7 Hz,1H), 8.34 (dd, J = 8.8, d₄-MeOH 1.9 Hz, 1H), 8.19 (d, J = 8.8 Hz, 1H),7.82 (d, J = 5.0 Hz, 1H), 7.63-7.71 (m, 5H), 7.46 (dt, J = 8.4, 4.3 Hz,1H), 6.84 (s, 1H) 114 300 MHz 8.87 (d, J = 1.8 Hz, 1H), 8.51 (d, J = 4.7Hz, 1H), 8.25 (dd, J = 8.7, d₄-MeOH 2.1 Hz, 1H), 8.18 (d, J = 7.2 Hz,1H), 7.75 (d, J = 8.8 Hz, 1H), 7.58-7.71 (m, 5H), 7.45 (dt, J = 8.5, 4.4Hz, 1H), 6.79 (s, 1H), 6.56 (d, J = 7.3 Hz, 1H) 115 400 MHz 9.52 (d, J =7.6 Hz, 1H), 8.93-8.99 (m, 2H), 8.59 (s, 1H), DMSO-d₆ 8.41 (d, J = 8.1Hz, 1H), 8.21 (d, J = 8.0 Hz, 1H), 8.03 (s, 2H), 7.62 (m, 2H), 7.27 (d,J = 8 Hz, 2H), 7.18 (d, J = 8 Hz, 2H), 7.68 (d, J = 7.6 Hz, 1H), 2.59(q, J = 8 Hz, 2H), 1.15 (t, J = 8 Hz, 3H) 116 300 MHz 8.94 (d, J = 4.8Hz, 1H), 8.91 (d, J = 1.6 Hz, 1H), 8.64 (d, J = 6.9 Hz, d₄-MeOH 1H),8.39 (dd, J = 8.9, 2.0 Hz, 1H), 8.16-8.27 (m, 1H), 7.98 (d, J = 9.1 Hz,1H), 7.53-7.70 (m, 5H), 7.03 (d, J = 6.9 Hz, 1H), 6.97 (s, 1H) 117 300MHz 8.91 (d, J = 4.4 Hz, 1H), 8.11-8.27 (m, 2H), 7.84 (d, J = 7.9 Hz,d₄-MeOH 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.49-7.68 (m, 5H), 7.23 (t, J =7.9 Hz, 1H), 6.89 (s, 1H) 118 300 MHz 8.88 (d, J = 4.2 Hz, 1H), 8.18 (d,J = 7.9 Hz, 1H), 7.87 (d, J = 7.9 Hz, d₄-MeOH 1H), 7.64 (s, 4H), 7.55(dd, J = 7.7, 4.9 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.33 (d, J = 6.6Hz, 1H), 7.15 (t, J = 7.2 Hz, 1H), 6.90 (s, 1H) 119 300 MHz 8.93 (d, J =4.2 Hz, 1H), 8.20 (d, J = 8.2 Hz, 1H), 7.52-7.74 (m, d₄-MeOH 2H),7.19-7.36 (m, 2H), 6.63 (s, 1H), 4.28-4.45 (m, 1H), 3.96-4.10 (m, 1H),3.81-3.96 (m, 1H), 2.15-2.35 (m, 1H), 1.74-2.02 (m, 3H) 120 300 MHz 8.91(d, J = 2.3 Hz, 1H), 8.60 (s, 1H), 8.46-8.54 (m, 2H), d₄-MeOH 8.10 (dd,J = 8.6, 1.7 Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.58-7.72 (m, 5H), 7.46(dt, J = 8.4, 4.4 Hz, 1H), 6.82 (s, 1H) 121 300 MHz 8.91 (d, J = 4.5 Hz,1H), 8.19 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 8.5 Hz, d₄-MeOH 2H),7.49-7.68 (m, 7H), 6.92 (s, 1H), 1.53 (s, 6H) 122 300 MHz 8.90 (d, J =4.4 Hz, 1H), 8.19 (d, J = 7.2 Hz, 1H), 7.84 (d, J = 8.5 Hz, d₄-MeOH 2H),7.50-7.67 (m, 7H), 6.90 (s, 1H) 123 300 MHz 8.92 (d, J = 4.1 Hz, 1H),8.11-8.29 (m, 1H), 7.52-7.71 (m, d₄-MeOH 2H), 7.28 (d, J = 9.9 Hz, 2H),6.63 (s, 1H), 4.37 (dd, J = 8.3, 5.6 Hz, 1H), 3.77-4.04 (m, 2H),2.14-2.35 (m, 1H), 1.70-2.03 (m, 3H) 124 600 MHz 9.32 (d, J = 7.6 Hz,1H), 8.92 (d, J = 4.7 Hz, 1H), 8.71 (d, J = 2.1 Hz, DMSO-d₆ 1H),8.28-8.17 (m, 2H), 7.61 (dd, J = 7.9, 4.9 Hz, 1H), 7.34 (dd, J = 8.6,5.5 Hz, 2H), 7.17 (t, J = 8.9 Hz, 2H), 6.87 (d, J = 8.7 Hz, 1H), 6.71(d, J = 7.5 Hz, 1H), 3.90 (s, 3H) 125 300 MHz 8.50 (d, J = 4.7 Hz, 1H),8.40 (d, J = 8.6 Hz, 1H), 8.23 (d, J = 7.2 Hz, d₄-MeOH 1H), 8.18 (d, J =1.2 Hz, 1H), 7.96 (dd, J = 8.6, 1.5 Hz, 1H), 7.59-7.72 (m, 5H), 7.46(dt, J = 8.6, 4.4 Hz, 1H), 6.79 (s, 1H), 6.58 (d, J = 7.2 Hz, 1H) 126600 MHz 9.22 (d, J = 7.2 Hz, 1H), 8.92 (d, J = 4.2 Hz, 1H), 8.23 (d, J =7.8 Hz, DMSO-d₆ 1H), 7.89 (d, J = 7.2 Hz, 2H), 7.61 (dd, J = 7.8, 4.8Hz, 1H), 7.54 (dd, J = 7.8, 1.2 Hz, 1H), 7.45 (t, J = 7.2 Hz, 2H),7.34-7.37 (m, 2H), 7.16 (d, J = 9 Hz, 2H), 6.71 (d, J = 7.8 Hz, 1H) 127300 MHz 8.91 (d, J = 4.2 Hz, 1H), 8.20 (d, J = 7.9 Hz, 1H), 7.78 (d, J =8.2 Hz, d₄-MeOH 2H), 7.50-7.71 (m, 2H), 7.23-7.45 (m, 4H), 6.89 (s, 1H),2.96 (dt, J = 13.6, 6.8 Hz, 1H), 1.25 (d, J = 6.9 Hz, 6H) 128 300 MHz9.22 (dd, J = 4.4, 1.8 Hz, 1H), 9.00 (d, J = 4.7 Hz, 1H), d₄-MeOH8.64-8.76 (m, 2H), 8.41 (d, J = 8.3 Hz, 1H), 8.22 (d, J = 7.9 Hz, 1H),7.84 (dd, J = 8.2, 4.4 Hz, 1H), 7.56-7.72 (m, 5H), 6.94 (s, 1H) 129 300MHz 9.23 (dd, J = 4.5, 1.8 Hz, 1H), 9.01 (d, J = 4.4 Hz, 1H), d₄-MeOH8.63-8.76 (m, 2H), 8.42 (d, J = 8.3 Hz, 1H), 8.24 (d, J = 8.0 Hz, 1H),7.85 (dd, J = 8.3, 4.5 Hz, 1H), 7.59-7.72 (m, 2H), 7.40-7.53 (m, 2H),6.91 (s, 1H) 130 300 MHz 9.31 (d, J = 4.2 Hz, 1H), 8.96 (d, J = 4.1 Hz,1H), 8.81 (d, J = 8.3 Hz, CDCl₃ 1H), 8.49-8.69 (m, 3H), 8.35 (dd, J =8.9, 1.8 Hz, 1H), 8.11 (d, J = 7.0 Hz, 1H), 7.90 (dd, J = 8.3, 4.8 Hz,1H), 7.49-7.64 (m, 2H), 7.38 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 11.4 Hz,1H), 6.89 (d, J = 7.6 Hz, 1H) 131 300 MHz 9.26 (br. s., 1H), 8.77-9.14(m, 4H), 8.39 (d, J = 8.6 Hz, 1H), CDCl₃ 8.22 (d, J = 8.6 Hz, 1H),7.91-8.16 (m, 2H), 7.46-7.65 (m, 2H), 7.28-7.46 (m, 2H), 6.84 (d, J =7.0 Hz, 1H) 132 300 MHz 8.85-9.00 (m, 2 H), 8.52 (s, 1 H), 8.42 (d, J =8.3 Hz, 1 H), d₄-MeOH 8.21 (d, J = 8.0 Hz, 1 H), 7.88-8.12 (m, 2 H),7.48-7.73 (m, 6 H), 6.99 (s, 1 H) 133 300 MHz 8.93 (d, J = 4.1 Hz, 2 H),8.38-8.56 (m, 2 H), 8.15-8.28 (m, 2 d₄-MeOH H), 7.96-8.15 (m, 1 H),7.50-7.71 (m, 6 H), 6.99 (s, 1 H) 134 400 MHz 8.95 (d, J = 7.4 Hz, 1H),8.90 (d, J = 4.7 Hz, 1H), 8.51 (d, J = 2.0 Hz, DMSO-d₆ 1H), 8.24 (d, J =7.8 Hz, 1H), 7.86 (dd, J = 8.6, 2.3 Hz, 1H), 7.66-7.73 (m, J = 8.2 Hz,2H), 7.61 (dd, J = 7.8, 4.7 Hz, 1H), 7.46-7.55 (m, J = 7.8 Hz, 2H), 6.78(d, J = 7.8 Hz, 1H), 6.51 (s, 2H), 6.40 (d, J = 8.6 Hz, 1H) 135 300 MHz8.90 (d, J = 3.9 Hz, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.30 (d, J = 7.6 Hz,CDCl₃ 1H), 8.00-8.16 (m, 2H), 7.46-7.65 (m, 5H), 7.41 (d, J = 8.2 Hz,1H), 6.85 (d, J = 7.6 Hz, 1H) 136 300 MHz 8.87 (d, J = 3.9 Hz, 1H), 8.75(d, J = 7.6 Hz, 1H), 8.00 (d, J = 8.0 Hz, CDCl₃ 1H), 7.62-7.74 (m, J =8.2 Hz, 2H), 7.51-7.61 (m, J = 8.3 Hz, 2H), 7.43 (dd, J = 8.0, 4.9 Hz,1H), 7.37 (s, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.34 (br s, 2H) 137 400 MHz9.38 (d, J = 7.4 Hz, 1H), 8.90 (d, J = 4.3 Hz, 1H), 8.66 (s, 1H),DMSO-d₆ 8.25 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 7.8 Hz, 2H), 7.55-7.65(m, 3H), 7.51 (d, J = 7.8 Hz, 3H), 6.74 (d, J = 7.4 Hz, 1H), 2.34 (s,3H) 138 300 MHz 8.89 (d, J = 3.8 Hz, 1H), 7.93-8.11 (m, 2H), 7.58 (dd, J= 3.7, CDCl₃ 1.1 Hz, 1H), 7.54 (s, 4H), 7.43-7.50 (m, 2H), 7.08 (dd, J =5.0, 3.8 Hz, 1H), 6.85 (d, J = 7.9 Hz, 1H) 139 400 MHz 9.35 (d, J = 7.4Hz, 1H), 8.91 (d, J = 4.3 Hz, 1H), 8.26 (d, J = 7.4 Hz, DMSO-d₆ 1H),8.12 (s, 1H), 7.67-7.76 (m, 3H), 7.63 (dd, J = 7.8, 5.1 Hz, 1H),7.47-7.56 (m, 3H), 6.75 (d, J = 7.4 Hz, 1H), 6.37 (s, 2H) 140 300 MHz8.90 (d, J = 3.8 Hz, 1H), 8.27 (d, J = 7.6 Hz, 1H), 8.07-8.14 (m, CDCl₃2H), 8.05 (d, J = 6.7 Hz, 1H), 7.83-7.94 (m, 2H), 7.55 (s, 4H), 7.48(dd, J = 7.7, 4.8 Hz, 1H), 6.89 (d, J = 7.7 Hz, 1H), 3.94 (s, 3H) 141300 MHz 8.98 (d, J = 4.2 Hz, 1H), 8.50 (d, J = 7.5 Hz, 1H), 8.13-8.18(m, CDCl₃ 3H), 7.95 (d, J = 8.5 Hz, 2H), 7.49-7.69 (m, 5H), 6.95 (d, J =7.3 Hz, 1H) 142 300 MHz 8.84 (d, J = 4.8 Hz, 1H), 8.00 (d, J = 7.5 Hz,1H), 7.37-7.60 (m, CDCl₃ 6H), 6.66 (d, J = 7.6 Hz, 1H), 3.97-4.15 (m,1H), 3.89 (d, J = 13.3 Hz, 1H), 2.95 (dd, J = 13.3, 10.4 Hz, 1H), 2.82(br. s., 1H), 2.33 (d, J = 3.8 Hz, 1H), 1.88 (br. s., 1H), 1.58-1.81 (m,2H), 1.43 (d, J = 2.2 Hz, 9H) 143 400 MHz 13.13 (br. s., 1H), 8.81-8.99(m, 2H), 8.34 (br. s., 1H), 8.25 (d, DMSO-d₆ J = 8.2 Hz, 1H), 7.98 (br.s., 1H), 7.66-7.75 (m, J = 8.2 Hz, 2H), 7.62 (dd, J = 8.0, 4.9 Hz, 1H),7.44-7.51 (m, J = 8.2 Hz, 2H), 6.81 (d, J = 7.8 Hz, 1H) 144 400 MHz 9.44(d, J = 8.6 Hz, 1H), 9.03 (d, J = 4.3 Hz, 1H), 8.30 (d, J = 8.2 Hz,DMSO-d₆ 1H), 7.80-7.86 (m, 1H), 7.64-7.76 (m, 3H), 7.54 (d, J = 8.2 Hz,2H), 7.28 (dd, J = 8.6, 4.3 Hz, 1H), 7.18 (dd, J = 8.6, 1.2 Hz, 1H),6.83 (br. s., 2H), 6.71 (d, J = 8.6 Hz, 1H) 145 400 MHz 8.96 (d, J = 8.2Hz, 1H), 8.86 (d, J = 4.3 Hz, 1H), 8.73 (s, 1H), DMSO-d₆ 8.22 (d, J =7.8 Hz, 1H), 7.62-7.69 (m, J = 8.2 Hz, 2H), 7.59 (dd, J = 7.8, 4.7 Hz,1H), 7.31-7.39 (m, J = 8.2 Hz, 2H), 6.58 (d, J = 7.8 Hz, 1H), 2.96 (q, J= 7.2 Hz, 2H), 2.52-2.61 (m, 2H), 2.23 (s, 3H) 146 400 MHz 9.02 (d, J =4.7 Hz, 1H), 8.97 (d, J = 8.6 Hz, 1H), 8.30 (d, J = 7.8 Hz, DMSO-d₆ 1H),7.63-7.77 (m, 3H), 7.54 (d, J = 8.2 Hz, 2H), 7.39 (s, 1H), 7.01 (s, 1H),6.66 (d, J = 8.6 Hz, 1H), 3.93 (s, 3H) 147 300 MHz 9.33 (s, 1H), 9.16(s, 2H), 8.91 (d, J = 4.2 Hz, 1H), 8.40 (d, J = 7.6 Hz, CDCl₃ 1H), 8.06(d, J = 8.2 Hz, 1H), 7.56 (s, 4H), 7.51 (dd, J = 8.1, 4.8 Hz, 1H), 6.86(d, J = 7.6 Hz, 1H) 148 300 MHz 8.90 (d, J = 4.1 Hz, 1H), 8.74 (d, J =1.8 Hz, 2H), 8.31 (d, J = 8.8 Hz, CDCl₃ 1H), 8.23 (d, J = 7.7 Hz, 1H),8.16 (dd, J = 8.8, 2.3 Hz, 1H), 8.05 (d, J = 7.0 Hz, 1H), 7.55 (s, 4H),7.49 (dd, J = 7.8, 4.9 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 2.23 (s, 3H)149 400 MHz 8.92-9.06 (m, 2H), 8.30 (d, J = 8.2 Hz, 1H), 7.63-7.78 (m,DMSO-d₆ 3H), 7.55 (d, J = 8.2 Hz, 2H), 7.01-7.06 (m, 1H), 6.95-6.99 (m,1H), 6.81 (d, J = 8.2 Hz, 1H), 2.68-2.76 (m, 3H) 150 400 MHz 9.00 (d, J= 4.3 Hz, 1H), 8.96 (d, J = 8.2 Hz, 1H), 8.30 (d, J = 8.2 Hz, DMSO-d₆1H), 7.81 (d, J = 9.8 Hz, 1H), 7.63-7.76 (m, 4H), 7.53 (d, J = 8.2 Hz,2H), 6.94 (d, J = 9.8 Hz, 1H), 6.68 (d, J = 8.2 Hz, 1H) 151 400 MHz 9.34(d, J = 7.8 Hz, 1H), 9.03 (br. s., 1H), 8.31 (d, J = 7.8 Hz, DMSO-d₆1H), 7.65-7.78 (m, 4H), 7.58 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 5.5 Hz,1H), 6.76 (d, J = 8.2 Hz, 1H), 2.75 (s, 3H), 2.61 (s, 3H) 152 400 MHz8.77-8.95 (m, 2H), 8.14-8.31 (m, 1H), 7.66-7.72 (m, J = 8.2 Hz, DMSO-d₆2H), 7.60 (dd, J = 7.8, 4.7 Hz, 1H), 7.36-7.53 (m, J = 7.8 Hz, 2H), 6.57(d, J = 7.8 Hz, 1H), 3.75-3.92 (m, 2H), 3.21-3.31 (m, 2H), 2.56-2.67 (m,1H), 1.47-1.66 (m, 4H) 153 400 MHz 9.23 (d, J = 7.8 Hz, 1H), 8.94 (d, J= 4.7 Hz, 1H), 8.26 (d, J = 7.8 Hz, DMSO-d₆ 1H), 7.68-7.77 (m, J = 8.2Hz, 2H), 7.64 (dd, J = 7.8, 4.7 Hz, 1H), 7.46-7.55 (m, J = 7.8 Hz, 2H),7.27 (s, 1H), 6.58 (d, J = 8.2 Hz, 1H), 6.00 (s, 1H), 4.77-4.99 (m, 2H),2.15 (s, 3H) 154 400 MHz 9.21 (d, J = 8.2 Hz, 1H), 8.90 (d, J = 4.3 Hz,1H), 8.23 (d, J = 7.8 Hz, DMSO-d₆ 1H), 7.66-7.76 (m, J = 8.2 Hz, 2H),7.61 (dd, J = 8.0, 4.9 Hz, 1H), 7.43-7.53 (m, J = 7.8 Hz, 2H), 6.59 (d,J = 7.8 Hz, 1H), 4.25 (t, J = 8.0 Hz, 2H), 3.84-4.03 (m, 2H) 155 300 MHz8.83 (d, J = 3.9 Hz, 1H), 8.36 (br. s., 1H), 8.01 (d, J = 8.0 Hz, CDCl₃1H), 7.85 (d, J = 8.0 Hz, 1H), 7.36-7.61 (m, 5H), 7.05 (s, 1H), 6.64 (d,J = 7.5 Hz, 1H), 2.90-3.08 (m, 2H), 2.72 (d, J = 6.6 Hz, 2H) 156 300 MHz8.95 (d, J = 3.9 Hz, 1H), 8.16-8.32 (m, 3H), 8.11 (td, J = 7.8, d₄-MeOH1.2 Hz, 1H), 7.96 (s, 1H), 7.88 (td, J = 7.7, 1.1 Hz, 1H), 7.59-7.79 (m,2H), 7.43-7.56 (m, 2H), 7.01 (s, 1H), 3.11 (d, J = 7.5 Hz, 2H),2.19-2.44 (m, 1H), 1.06 (d, J = 6.6 Hz, 6H) 157 400 MHz 8.95 (dd, J =8.0, 3.7 Hz, 1H), 8.89 (d, J = 4.7 Hz, 1H), 8.24 (d, DMSO-d₆ J = 7.8 Hz,1H), 7.64-7.75 (m, J = 8.2 Hz, 2H), 7.60 (dd, J = 7.8, 5.1 Hz, 1H),7.38-7.52 (m, J = 7.4 Hz, 2H), 6.59 (d, J = 7.8 Hz, 1H), 3.63-3.74 (m,2H), 3.59 (qd, J = 7.6, 2.3 Hz, 1H), 3.15-3.29 (m, 1H), 2.39-2.49 (m,1H), 2.21-2.39 (m, 2H), 1.83-1.96 (m, 1H), 1.38-1.53 (m, 1H) 158 400 MHz11.87 (br. s., 1H), 9.08 (d, J = 8.2 Hz, 1H), 8.91 (d, J = 4.3 Hz,DMSO-d₆ 1H), 8.24 (d, J = 7.4 Hz, 1H), 7.65-7.72 (m, J = 8.2 Hz, 2H),7.61 (dd, J = 8.0, 4.9 Hz, 2H), 7.44-7.49 (m, J = 8.2 Hz, 2H), 6.90 (br.s., 1H), 6.60 (d, J = 8.2 Hz, 1H), 3.48 (br. s., 2H) 159 400 MHz 9.01(d, J = 4.7 Hz, 1H), 8.65 (d, J = 8.2 Hz, 1H), 8.30 (d, J = 7.8 Hz,DMSO-d₆ 1H), 7.63-7.77 (m, 3H), 7.51 (d, J = 8.2 Hz, 2H), 6.66 (d, J =8.6 Hz, 1H), 6.26 (br. s., 2H) 160 400 MHz 9.35 (d, J = 7.8 Hz, 1H),8.94 (d, J = 4.3 Hz, 1H), 8.26 (d, J = 8.2 Hz, DMSO-d₆ 1H), 7.69-7.76(m, J = 8.2 Hz, 2H), 7.64 (dd, J = 7.8, 4.7 Hz, 1H), 7.46-7.56 (m, J =7.8 Hz, 2H), 6.96 (s, 1H), 6.67 (s, 1H), 6.57 (d, J = 7.8 Hz, 1H),4.61-4.83 (m, 2H), 2.13 (s, 3H) 161 300 MHz 9.12 (br. s., 1H), 8.84 (d,J = 3.9 Hz, 1H), 8.52 (d, J = 7.5 Hz, CDCl₃ 1H), 7.99 (d, J = 7.9 Hz,1H), 7.47-7.58 (m, 4H), 7.43 (dd, J = 7.8, 4.8 Hz, 1H), 7.32 (s, 1H),6.60 (d, J = 7.3 Hz, 1H), 4.93-5.23 (m, 2H) 162 400 MHz 8.81-8.99 (m,2H), 8.25 (dd, J = 7.4, 2.7 Hz, 1H), 8.05 (dd, J = 19.0, DMSO-d₆ 7.6 Hz,1H), 7.69 (dd, J = 8.2, 3.1 Hz, 2H), 7.58-7.66 (m, 1H), 7.45 (t, J = 7.4Hz, 2H), 6.54 (dd, J = 17.8, 8.0 Hz, 1H), 4.32-4.56 (m, 1H), 1.81 (d, J= 7.4 Hz, 3H), 1.06-1.29 (m, 3H) 163 400 MHz 9.06-9.16 (m, 1H),8.87-8.95 (m, 1H), 8.24 (d, J = 7.8 Hz, DMSO-d₆ 1H), 7.67-7.74 (m, J =8.2 Hz, 2H), 7.62 (dd, J = 7.8, 4.7 Hz, 1H), 7.54 (d, J = 9.4 Hz, 1H),7.42-7.49 (m, J = 8.2 Hz, 2H), 6.58 (dd, J = 7.8, 3.9 Hz, 1H), 3.41-3.49(m, 1H), 3.11-3.25 (m, 1H), 2.29 (dd, J = 7.8, 5.5 Hz, 1H), 2.24 (t, J =8.4 Hz, 1H) 164 400 MHz 8.75 (br. s., 1H), 7.98 (d, J = 6.8 Hz, 1H),7.14-7.61 (m, 9H), CDCl₃ 6.66 (d, J = 6.8 Hz, 1H), 3.65 (br. s., 2H) 165400 MHz 9.15 (d, J = 4.9 Hz, 1H), 8.43 (d, J = 7.8 Hz, 1H), 8.00 (s,2H), d₄-MeOH 7.84-7.88 (m, 2H), 7.81-7.84 (m, 1H), 7.76-7.81 (m, 2H),7.15 (s, 1H), 7.07 (d, J = 8.6 Hz, 2H) 166 400 MHz 8.53 (d, J = 4.7 Hz,1H), 8.16 (s, 2H), 7.91 (d, J = 8.2 Hz, 1H), d₄-MeOH 7.60-7.72 (m, 6H),7.49 (dt, J = 8.5, 4.4 Hz, 1H), 6.82 (s, 1H) 167 400 MHz 8.49 (d, J =4.5 Hz, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.86 (d, J = 8.4 Hz, d₄-MeOH 2H),7.58-7.69 (m, 5H), 7.45 (dt, J = 8.5, 4.4 Hz, 1H), 6.72-6.79 (m, 1H) 168400 MHz 8.93 (d, J = 4.9 Hz, 1H), 8.17-8.25 (m, 2H), 8.15 (d, J = 8.0Hz, d₄-MeOH 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.62-7.71 (m, 3H), 7.54-7.61(m, 3H), 6.92 (s, 1H) 169 400 MHz 8.37 (d, J = 4.7 Hz, 1H), 7.82 (d, J =7.8 Hz, 1H), 7.42-7.53 (m, d₄-MeOH 5H), 7.33-7.42 (m, 1H), 7.28 (dt, J =8.6, 4.4 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.91 (t, J = 7.5 Hz, 1H),6.49 (s, 1H), 3.97 (s, 3H) 170 400 MHz 8.99 (d, J = 3.9 Hz, 2H), 8.68(d, J = 1.6 Hz, 1H), 8.53 (d, J = 4.5 Hz, d₄-MeOH 1H), 8.28-8.35 (m,1H), 8.17-8.26 (m, 1H), 7.61-7.75 (m, 5H), 7.48 (dt, J = 8.5, 4.4 Hz,1H), 6.85 (s, 1H) 171 400 MHz 8.94 (d, J = 4.1 Hz, 1H), 8.22 (dd, J =8.0, 1.0 Hz, 1H), d₄-MeOH 7.81-7.92 (m, 2H), 7.52-7.69 (m, 5H),6.97-7.06 (m, 2H), 6.94 (s, 1H), 3.87 (s, 3H) 172 400 MHz 8.50 (d, J =4.5 Hz, 1H), 7.90 (d, J = 9.0 Hz, 2H), 7.58-7.71 (m, d₄-MeOH 5H), 7.45(dt, J = 8.5, 4.4 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 6.75 (s, 1H), 3.87(s, 3H) 173 400 MHz 8.55 (d, J = 4.7 Hz, 1H), 8.24 (d, J = 2.7 Hz, 1H),7.97 (d, J = 8.6 Hz, d₄-MeOH 1H), 7.60-7.70 (m, 5H), 7.47 (dt, J = 8.5,4.4 Hz, 1H), 7.28 (dd, J = 8.5, 2.8 Hz, 1H), 6.67 (d, J = 1.6 Hz, 1H)174 400 MHz 9.22 (d, J = 7.6 Hz, 1H), 8.93 (d, J = 4.5 Hz, 1H), 8.21 (d,J = 7.8 Hz, d₄-MeOH 1H), 7.92 (d, J = 8.8 Hz, 2H), 7.50-7.71 (m, 5H),7.23 (d, J = 8.6 Hz, 2H), 6.94 (d, J = 7.6 Hz, 1H), 2.31 (s, 3H) 175 400MHz 8.96 (d, J = 4.3 Hz, 1H), 8.24 (dd, J = 8.0, 1.0 Hz, 1H), 8.12 (dd,d₄-MeOH J = 12.6, 0.9 Hz, 2H), 7.88 (dd, J = 8.5, 0.7 Hz, 1H), 7.56-7.72(m, 6H), 7.00 (s, 1H) 176 400 MHz 9.00 (d, J = 4.7 Hz, 1H), 8.22 (d, J =7.8 Hz, 1H), 8.01 (dd, J = 7.8, d₄-MeOH 1.6 Hz, 1H), 7.59-7.69 (m, 5H),7.50-7.57 (m, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H),6.91 (s, 1H), 4.07 (s, 3H) 177 400 MHz 10.90 (s, 1H), 10.83 (s, 1H),9.20 (d, J = 7.6 Hz, 1H), 8.45 (d, J = 4.7 Hz, d₆₋DMSO 1H), 7.69-7.83(m, 3H), 7.58-7.66 (m, 3H), 7.53 (s, 1H), 7.48 (dt, J = 8.4, 4.3 Hz,1H), 6.97 (d, J = 8.2 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H) 178 400 MHz 8.94(d, J = 4.7 Hz, 1H), 8.65-8.76 (m, 2H), 8.23 (d, J = 8.0 Hz, d₄-MeOH1H), 7.79-7.88 (m, 2H), 7.65-7.70 (m, 2H), 7.56-7.64 (m, 3H), 6.94 (s,1H) 179 400 MHz 8.95 (d, J = 4.3 Hz, 1H), 8.52 (s, 1H), 8.22 (dd, J =7.2, 4.3 Hz, d₄-MeOH 2H), 8.09 (d, J = 7.8 Hz, 1H), 7.51-7.71 (m, 6H),6.90-7.01 (m, 1H) 180 400 MHz 8.50 (d, J = 4.7 Hz, 1H), 7.91 (d, J = 7.2Hz, 2H), 7.61-7.71 (m, d₄-MeOH 5H), 7.54-7.61 (m, 1H), 7.40-7.54 (m,3H), 6.76 (s, 1H) 181 400 MHz 8.94 (d, J = 3.9 Hz, 1H), 8.22 (d, J = 7.2Hz, 1H), 7.97-8.06 (m, d₄-MeOH 2H), 7.81-7.90 (m, 2H), 7.64-7.70 (m,2H), 7.57-7.63 (m, 3H), 6.94 (s, 1H) 182 400 MHz 8.94 (s, 2H), 8.68 (s,1H), 8.45 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H), d₄-MeOH 7.63-7.69 (m, 2H),7.55-7.62 (m, 3H), 6.93 (s, 1H), 2.51 (s, 3H) 183 400 MHz 8.93 (d, J =4.5 Hz, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.93 (dd, J = 8.8, d₄-MeOH 5.3Hz, 2H), 7.62-7.68 (m, 2H), 7.54-7.62 (m, 3H), 7.21 (t, J = 8.7 Hz, 2H),6.93 (s, 1H) 184 400 MHz 8.52 (d, J = 4.7 Hz, 1H), 8.27-8.33 (m, 1H),8.21 (dt, J = 7.9, d₄-MeOH 1.4 Hz, 1H), 7.95 (dt, J = 7.8, 1.3 Hz, 1H),7.58-7.75 (m, 6H), 7.40-7.53 (m, 1H), 6.79 (s, 1H) 185 400 MHz 8.92 (d,J = 4.3 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.78-7.91 (m, d₄-MeOH 2H),7.61-7.68 (m, 2H), 7.54-7.61 (m, 3H), 7.46-7.51 (m, 2H), 6.91 (s, 1H)186 400 MHz 8.93 (d, J = 4.7 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H),7.62-7.67 (m, d₄-MeOH 2H), 7.54-7.62 (m, 3H), 7.26-7.34 (m, 1H), 7.22(s, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.90-6.98 (m, 2H), 2.98 (s, 6H) 187400 MHz 8.50 (d, J = 4.7 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.59-7.69(m, d₄-MeOH 6H), 7.52 (td, J = 8.0, 5.8 Hz, 1H), 7.45 (dt, J = 8.5, 4.4Hz, 1H), 7.32 (td, J = 8.4, 2.0 Hz, 1H), 6.76 (br. s., 1H) 188 400 MHz8.99-9.05 (m, 1H), 8.94 (d, J = 4.1 Hz, 1H), 8.71 (dd, J = 4.9, d₄-MeOH1.6 Hz, 1H), 8.26-8.33 (m, 1H), 8.22 (dd, J = 7.9, 0.9 Hz, 1H),7.64-7.69 (m, 2H), 7.58-7.63 (m, 3H), 7.56 (ddd, J = 7.9, 5.0, 0.8 Hz,1H), 6.96 (s, 1H) 189 400 MHz 8.94 (d, J = 4.5 Hz, 1H), 8.50 (s, 1H),8.21 (t, J = 7.5 Hz, 2H), d₄-MeOH 8.10 (d, J = 7.6 Hz, 1H), 7.53-7.71(m, 6H), 6.95 (s, 1H), 3.95 (s, 3H) 190 400 MHz 8.96 (d, J = 4.3 Hz,1H), 8.24 (s, 1H), 8.20-8.23 (m, 1H), d₄-MeOH 7.60-7.70 (m, 3H),7.55-7.59 (m, 2H), 6.87 (s, 1H), 2.47 (s, 3H) 191 400 MHz 8.94 (d, J =4.1 Hz, 1H), 8.23 (d, J = 8.2 Hz, 1H), 7.63-7.68 (m, d₄-MeOH 2H),7.55-7.63 (m, 3H), 7.34-7.48 (m, 3H), 7.13 (dt, J = 6.7, 1.3 Hz, 1H),6.94 (s, 1H), 3.86 (s, 3H) 192 400 MHz 8.95 (d, J = 4.7 Hz, 1H), 8.21(d, J = 8.2 Hz, 1H), 7.51-7.69 (m, d₄-MeOH 6H), 6.86 (s, 1H), 6.73 (d, J= 2.3 Hz, 1H), 3.96 (s, 3H) 193 400 MHz 8.51 (d, J = 4.7 Hz, 1H), 7.91(d, J = 7.2 Hz, 2H), 7.62-7.70 (m, d₄-MeOH 5H), 7.55-7.61 (m, 1H),7.42-7.54 (m, 3H), 6.76 (s, 1H) 194 400 MHz 8.71 (d, J = 4.3 Hz, 1H),8.54 (d, J = 4.5 Hz, 1H), 8.10 (d, J = 7.8 Hz, d₄-MeOH 1H), 7.97 (td, J= 7.7, 1.7 Hz, 1H), 7.55-7.70 (m, 6H), 7.46 (dt, J = 8.5, 4.4 Hz, 1H),6.68 (s, 1H) 195 400 MHz 9.67 (d, J = 7.6 Hz, 1H), 9.01 (dd, J = 4.1,1.8 Hz, 1H), d₆₋DMSO 8.59-8.71 (m, 2H), 8.45 (dd, J = 8.3, 0.9 Hz, 1H),8.17 (dd, J = 8.1, 1.5 Hz, 1H), 8.08 (s, 2H), 7.71-7.80 (m, 2H),7.59-7.69 (m, 3H), 7.38 (dd, J = 8.0, 4.7 Hz, 1H), 6.88 (d, J = 7.6 Hz,1H) 196 400 MHz 8.94 (d, J = 4.1 Hz, 1H), 8.22 (d, J = 7.0 Hz, 1H),7.73-7.84 (m, d₄-MeOH 2H), 7.51-7.69 (m, 5H), 6.95 (s, 1H), 6.71-6.81(m, 2H), 3.05 (s, 6H) 197 400 MHz 8.90 (d, J = 4.5 Hz, 1H), 8.20 (d, J =8.0 Hz, 1H), 7.83 (d, J = 7.6 Hz, d₄-MeOH 1H), 7.71-7.79 (m, 2H),7.60-7.70 (m, 5H), 7.57 (dd, J = 7.8, 4.9 Hz, 1H), 6.92 (s, 1H) 198 400MHz 8.86 (d, J = 2.2 Hz, 1H), 8.61 (d, J = 2.2 Hz, 1H), 8.52 (d, J = 4.7Hz, d₄-MeOH 1H), 7.59-7.73 (m, 5H), 7.47 (dt, J = 8.5, 4.4 Hz, 1H), 6.78(s, 1H) 199 400 MHz 8.78 (d, J = 4.1 Hz, 1H), 7.98-8.11 (m, 2H), 7.50(d, J = 8.4 Hz, d₄-MeOH 2H), 7.42-7.47 (m, 2H), 7.40 (d, J = 8.2 Hz,2H), 6.77 (s, 1H), 6.74 (d, J = 1.0 Hz, 1H) 200 400 MHz 8.51 (d, J = 4.7Hz, 1H), 8.02-8.10 (m, 2H), 7.85-7.91 (m, d₄-MeOH 2H), 7.62-7.72 (m,5H), 7.47 (dt, J = 8.6, 4.4 Hz, 1H), 6.78 (s, 1H) 201 400 MHz 8.72 (dd,J = 5.3, 0.8 Hz, 1H), 8.15-8.25 (m, 2H), 8.08 (dd, J = 9.6, d₄-MeOH 2.7Hz, 1H), 7.71-7.78 (m, 3H), 7.69 (dd, J = 7.0, 5.9 Hz, 1H), 7.61 (d, J =8.2 Hz, 2H), 6.54-6.63 (m, 2H) 202 400 MHz 8.95-9.05 (m, 2H), 8.69 (d, J= 2.0 Hz, 1H), 8.50-8.58 (m, d₄-MeOH 1H), 8.32 (dd, J = 8.8, 2.0 Hz,1H), 8.18-8.25 (m, 1H), 7.61-7.75 (m, 5H), 7.49 (dt, J = 8.5, 4.4 Hz,1H), 6.86 (s, 1H) 203 400 MHz 9.05 (d, J = 1.8 Hz, 1H), 8.71 (dd, J =5.0, 1.5 Hz, 1H), 8.49 (d, d₄-MeOH J = 4.7 Hz, 1H), 8.32 (dt, J = 8.0,2.0 Hz, 1H), 7.59-7.69 (m, 5H), 7.56 (dd, J = 7.8, 5.1 Hz, 1H), 7.45(dt, J = 8.5, 4.4 Hz, 1H), 6.78 (s, 1H) 204 400 MHz 8.99 (dd, J = 4.5,1.6 Hz, 1H), 8.60 (s, 1H), 8.52 (d, J = 6.1 Hz, d₄-MeOH 2H), 8.11 (s,2H), 7.61-7.74 (m, 6H), 7.47 (dt, J = 8.5, 4.4 Hz, 1H), 6.83 (s, 1H) 205400 MHz 8.99 (d, J = 4.7 Hz, 1H), 8.78 (d, J = 1.8 Hz, 1H), 8.12-8.29(m, d₄-MeOH 2H), 8.05 (d, J = 8.2 Hz, 1H), 7.55-7.68 (m, 5H), 6.87 (s,1H) 206 400 MHz 9.10 (d, J = 1.4 Hz, 1H), 8.92 (d, J = 4.5 Hz, 1H), 8.38(dd, J = 8.1, d₄-MeOH 2.2 Hz, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.97 (dd, J= 8.0, 0.6 Hz, 1H), 7.62-7.69 (m, 2H), 7.55-7.62 (m, 3H), 6.92 (s, 1H)207 400 MHz 8.55 (s, 1H), 8.50 (d, J = 4.7 Hz, 1H), 8.21 (d, J = 7.8 Hz,1H), d₄-MeOH 8.12 (d, J = 8.2 Hz, 1H), 7.55-7.70 (m, 6H), 7.45 (dt, J =8.6, 4.3 Hz, 1H), 6.77 (s, 1H) 208 400 MHz 8.92 (d, J = 4.7 Hz, 1H),8.20 (d, J = 7.8 Hz, 1H), 7.87 (s, 1H), d₄-MeOH 7.79 (d, J = 7.8 Hz,1H), 7.61-7.67 (m, 2H), 7.53-7.61 (m, 4H), 7.42-7.50 (m, 1H), 6.91 (d, J= 7.6 Hz, 1H) 209 400 MHz 8.50 (d, J = 4.7 Hz, 1H), 7.75 (d, J = 7.8 Hz,1H), 7.59-7.69 (m, d₄-MeOH 6H), 7.53 (td, J = 8.0, 5.8 Hz, 1H), 7.46(dt, J = 8.5, 4.4 Hz, 1H), 7.29-7.37 (m, 1H), 6.76 (s, 1H) 210 400 MHz8.97 (d, J = 4.9 Hz, 1H), 8.32 (d, J = 2.9 Hz, 1H), 8.21 (d, J = 7.2 Hz,d₄-MeOH 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.54-7.68 (m, 5H), 7.48 (dd, J =8.7, 2.8 Hz, 1H), 6.86 (s, 1H), 3.94 (s, 3H) 211 400 MHz 8.94 (d, J =4.1 Hz, 1H), 8.18-8.26 (m, 2H), 8.15 (d, J = 7.6 Hz, d₄-MeOH 1H), 7.88(d, J = 7.8 Hz, 1H), 7.64-7.74 (m, 3H), 7.55-7.64 (m, 3H), 6.96 (s, 1H)212 400 MHz 9.53 (dd, J = 2.2, 1.3 Hz, 1H), 9.36 (dd, J = 5.3, 1.2 Hz,1H), d₄-MeOH 8.93 (d, J = 4.5 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H), 8.06(dd, J = 5.4, 2.2 Hz, 1H), 7.63-7.68 (m, 2H), 7.55-7.62 (m, 3H), 6.92(s, 1H) 213 400 MHz 10.13 (s, 1H), 9.24 (d, J = 7.6 Hz, 1H), 8.45 (d, J= 4.7 Hz, 1H), d₆₋DMSO 7.92 (d, J = 8.8 Hz, 2H), 7.74-7.81 (m, 1H), 7.72(d, J = 8.2 Hz, 2H), 7.63 (d, J = 8.2 Hz, 2H), 7.48 (dt, J = 8.5, 4.4Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.73 (d, J = 7.6 Hz, 1H), 3.06 (s,3H) 214 400 MHz ¹H NMR (MeOH): 8.52 (d, J = 4.7 Hz, 1H), 7.61-7.71 (m,d₄-MeOH 5H), 7.36-7.53 (m, 4H), 7.10-7.19 (m, 1H), 6.77 (s, 1H), 3.87(s, 3H) 215 400 MHz 9.01 (d, J = 4.1 Hz, 1H), 8.17-8.28 (m, 2H),7.59-7.69 (m, d₄-MeOH 6H), 7.43-7.53 (m, 1H), 7.32 (t, J = 7.2 Hz, 1H),6.98 (s, 1H), 4.18 (s, 3H) 216 400 MHz 8.50 (d, J = 4.7 Hz, 1H), 8.47(s, 1H), 8.24 (d, J = 7.8 Hz, 1H), d₄-MeOH 8.15 (d, J = 7.8 Hz, 1H),7.77 (t, J = 7.8 Hz, 1H), 7.60-7.70 (m, 5H), 7.46 (dt, J = 8.5, 4.4 Hz,1H), 6.79 (s, 1H), 3.17 (s, 3H) 217 400 MHz 8.50 (d, J = 4.7 Hz, 1H),8.10-8.14 (m, 2H), 8.05-8.10 (m, d₄-MeOH 2H), 7.58-7.72 (m, 5H), 7.46(dt, J = 8.5, 4.4 Hz, 1H), 6.77 (s, 1H), 3.17 (s, 3H) 218 400 MHz 8.86(d, J = 4.3 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.4 Hz,d₄-MeOH 2H), 7.55 (dd, J = 7.8, 4.9 Hz, 1H), 7.48 (d, J = 8.2 Hz, 2H),7.20-7.35 (m, 5H), 6.70 (s, 1H), 3.64 (s, 2H) 219 400 MHz 8.94 (d, J =3.9 Hz, 1H), 8.22 (dd, J = 8.0, 1.2 Hz, 1H), d₄-MeOH 7.86-7.94 (m, 1H),7.80 (s, 1H), 7.64-7.68 (m, 2H), 7.56-7.63 (m, 4H), 7.47-7.53 (m, 1H),6.94 (s, 1H) 220 400 MHz 8.96 (d, J = 4.9 Hz, 1H), 8.54 (d, J = 1.8 Hz,1H), 8.22 (d, J = 7.2 Hz, d₄-MeOH 1H), 7.53-7.69 (m, 5H), 7.06 (d, J =2.0 Hz, 1H), 6.88 (s, 1H) 221 400 MHz 8.50 (d, J = 4.5 Hz, 1H), 8.23 (s,1H), 7.57-7.69 (m, 5H), d₄-MeOH 7.46 (dt, J = 8.5, 4.4 Hz, 1H), 6.65 (s,1H), 2.45 (s, 3H) 222 400 MHz 8.96 (d, J = 4.5 Hz, 1H), 8.23 (d, J = 8.0Hz, 1H), 8.10-8.15 (m, d₄-MeOH 1H), 7.86-7.98 (m, 2H), 7.64-7.70 (m,2H), 7.57-7.63 (m, 3H), 7.39-7.50 (m, 2H), 6.94 (s, 1H) 223 400 MHz 8.89(d, J = 4.1 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 7.8 Hz,d₄-MeOH 2H), 7.47-7.58 (m, 3H), 6.69 (s, 1H), 2.82-3.02 (m, 1H),2.48-2.72 (m, 1H), 2.24-2.45 (m, 2H), 1.14-2.18 (m, 5H) 224 400 MHz 8.89(d, J = 4.5 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 7.59-7.64 (m, d₄-MeOH2H), 7.55-7.59 (m, 1H), 7.51-7.55 (m, 2H), 6.74 (s, 1H), 3.57-3.78 (m,2H), 2.36-2.76 (m, 2H) 225 400 MHz 8.91 (d, J = 4.7 Hz, 1H), 8.18 (d, J= 8.0 Hz, 1H), 7.60-7.68 (m, d₄-MeOH 2H), 7.50-7.60 (m, 3H), 6.73 (s,1H), 3.64-4.17 (m, 4H), 3.21 (quin, J = 7.4 Hz, 1H), 2.00-2.21 (m, 2H)226 400 MHz 9.27 (d, J = 2.0 Hz, 1H), 9.19 (d, J = 2.2 Hz, 1H), 8.95 (d,J = 3.9 Hz, d₄-MeOH 1H), 8.81 (t, J = 2.1 Hz, 1H), 8.23 (d, J = 7.4 Hz,1H), 7.65-7.69 (m, 2H), 7.58-7.64 (m, 3H), 6.94-7.00 (m, 1H) 227 400 MHz8.94 (d, J = 4.1 Hz, 1H), 8.22 (dd, J = 8.1, 0.9 Hz, 1H), d₄-MeOH7.69-7.75 (m, 1H), 7.56-7.68 (m, 6H), 7.51 (td, J = 8.0, 5.6 Hz, 1H),7.28-7.37 (m, 1H), 6.94 (s, 1H) 228 400 MHz 9.00 (d, J = 4.5 Hz, 1H),8.68 (d, J = 4.7 Hz, 1H), 8.23 (d, J = 8.0 Hz, d₄-MeOH 1H), 8.14 (s,1H), 7.99 (td, J = 7.7, 1.6 Hz, 1H), 7.53-7.69 (m, 6H), 6.90 (s, 1H) 229400 MHz 8.91 (d, J = 4.5 Hz, 1H), 8.18 (d, J = 7.4 Hz, 1H), 7.64 (d, J =8.2 Hz, d₄-MeOH 2H), 7.50-7.60 (m, 3H), 6.71 (s, 1H), 3.95-4.09 (m, 2H),3.59-3.68 (m, 2H), 2.86-2.97 (m, 1H), 2.64 (d, J = 7.8 Hz, 2H), 1.44 (s,9H) 230 400 MHz 9.28 (d, J = 2.2 Hz, 1H), 8.97 (d, J = 3.9 Hz, 1H), 8.89(d, J = 1.6 Hz, d₄-MeOH 1H), 8.24 (d, J = 7.2 Hz, 1H), 8.11 (t, J = 9.1Hz, 2H), 7.84-7.97 (m, 1H), 7.57-7.77 (m, 6H), 7.03 (s, 1H) 231 400 MHz8.94 (d, J = 4.3 Hz, 1H), 8.20-8.25 (m, 1H), 7.96-8.02 (m, d₄-MeOH 2H),7.64-7.70 (m, 2H), 7.55-7.63 (m, 3H), 7.39 (d, J = 8.0 Hz, 2H), 6.94 (s,1H) 232 300 MHz 8.94 (d, J = 3.1 Hz, 1 H), 8.56 (s, 1 H), 8.43 (d, J =8.0 Hz, 1 H), d₄-MeOH 8.06 (s, 2 H), 7.53-7.74 (m, 6 H), 7.34 (dd, J =7.6, 5.0 Hz, 1 H), 6.91 (s, 1 H), 1.70 (t, J = 7.1 Hz, 1 H), 1.52 (s, 3H), 0.87-1.01 (m, 2 H), 0.83 (s, 3 H) 233 400 MHz 8.90-9.00 (m, 1 H),8.44-8.62 (m, 3 H), 8.25 (dd, J = 8.9, 1.9 Hz, d₄-MeOH 1 H), 8.13 (d, J= 8.8 Hz, 1 H), 7.52-7.73 (m, 6 H), 7.35 (dd, J = 7.7, 4.8 Hz, 1 H),6.95 (s, 1 H), 1.62-1.76 (m, 1 H), 1.54 (s, 3 H), 0.86-0.98 (m, 2 H),0.77-0.86 (m, 3 H) 234 400 MHz 8.94 (d, J = 4.5 Hz, 1 H), 8.20 (d, J =8.0 Hz, 1 H), d₄-MeOH 7.57-7.69 (m, 3 H), 7.51 (d, J = 8.0 Hz, 2 H),6.68 (s, 1 H), 4.28-4.42 (m, 1 H), 4.03 (q, J = 6.5 Hz, 1 H), 3.91 (q, J= 6.8 Hz, 1 H), 2.18-2.36 (m, 1 H), 1.74-2.01 (m, 3 H) 235 400 MHz 8.37(d, J = 4.5 Hz, 1H), 7.52-7.66 (m, 3H), 7.46 (d, J = 8.0 Hz, d₄-MeOH2H), 7.14-7.34 (m, 6H), 6.46 (s, 1H), 5.80 (ddt, J = 16.8, 10.4, 6.2 Hz,1H), 4.97 (d, J = 10.0 Hz, 1H), 4.89 (d, J = 17.2 Hz, 1H), 3.81 (q, J =7.0 Hz, 1H), 3.32-3.44 (m, 2H), 1.46 (d, J = 7.0 Hz, 3H) 236 400 MHz8.89-9.01 (m, 1 H), 8.56-8.61 (m, 1 H), 8.48-8.56 (m, 2 H), d₄-MeOH 8.23(dd, J = 8.9, 1.9 Hz, 1 H), 8.13 (d, J = 8.8 Hz, 1 H), 7.70 (d, J = 7.8Hz, 1 H), 7.54-7.66 (m, 5 H), 7.35 (dd, J = 7.6, 4.7 Hz, 1 H), 6.96 (s,1 H), 2.93 (d, J = 13.7 Hz, 1 H), 2.51-2.78 (m, 1 H), 1.03 (s, 9 H) 237300 MHz 8.86 (d, J = 4.5 Hz, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), d₄-MeOH7.28-7.67 (m, 10 H), 6.68 (s, 1 H), 3.38 (s, 3 H) 238 300 MHz 8.87 (d, J= 4.5 Hz, 1 H), 8.45 (s, 1 H), 8.40 (d, J = 4.5 Hz, 1 H), d₄-MeOH 8.14(d, J = 7.9 Hz, 1 H), 7.75 (d, J = 7.7 Hz, 1 H), 7.57-7.63 (m, 2 H),7.52-7.57 (m, 1 H), 7.44-7.52 (m, 2 H), 7.36 (dd, J = 7.7, 5.0 Hz, 1 H),6.68 (s, 1 H), 3.68 (s, 2 H) 239 400 MHz 9.11 (s, 1H), 8.92 (d, J = 3.9Hz, 1H), 8.52 (d, J = 1.5 Hz, 1H), CDCl₃ 8.32 (d, J = 7.7 Hz, 1H), 8.18(d, J = 8.5 Hz, 1H), 8.02-8.09 (m, 1H), 7.95 (dd, J = 8.6, 1.7 Hz, 1H),7.52-7.63 (m, 4H), 7.48 (dd, J = 7.7, 5.1 Hz, 1H), 6.93 (d, J = 7.7 Hz,1H) 240 400 MHz 8.85 (dd, J = 4.7, 1.2 Hz, 1H), 8.32 (d, J = 7.9 Hz,1H), 7.99 (dd, CDCl₃ J = 8.0, 1.0 Hz, 1H), 7.44-7.58 (m, 4H), 7.41 (dd,J = 7.7, 5.0 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H), 3.24 (s, 3H), 1.35 (s,3H), 1.35 (s, 3H) 241 400 MHz 8.84 (d, J = 4.2 Hz, 1H), 8.00 (d, J = 7.9Hz, 1H), 7.35-7.59 (m, CDCl₃ 6H), 6.69 (d, J = 7.7 Hz, 1H), 3.51 (d, J =6.9 Hz, 2H), 2.29-2.49 (m, 1H), 1.76-1.94 (m, 2H), 1.36-1.76 (m, 7H) 242400 MHz 8.87 (d, J = 4.2 Hz, 1H), 8.13 (d, J = 7.7 Hz, 1H), 7.49-7.61(m, CDCl₃ 4H), 7.46 (d, J = 8.3 Hz, 2H), 6.70 (d, J = 7.7 Hz, 1H),3.49-3.68 (m, 1H), 2.18 (tt, J = 11.9, 3.5 Hz, 1H), 1.86-2.10 (m, 3H),1.42-1.65 (m, 2H), 1.17-1.38 (m, 2H) 243 400 MHz 8.84 (d, J = 4.2 Hz,1H), 8.36 (d, J = 7.6 Hz, 1H), 8.05 (d, J = 7.2 Hz, CDCl₃ 1H), 7.35-7.62(m, 5H), 6.65 (d, J = 7.5 Hz, 1H), 1.54 (s, 3H), 1.51 (s, 3H) 244 300MHz 8.83 (d, J = 3.9 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.35-7.60 (m,CDCl₃ 6H), 6.68 (d, J = 7.9 Hz, 1H), 2.59 (t, J = 4.6 Hz, 1H), 2.20-2.38(m, 1H), 2.01-2.20 (m, 2H), 1.75 (d, J = 5.1 Hz, 3H), 1.48-1.66 (m, 2H)245 400 MHz 8.58 (d, J = 4.3 Hz, 1H), 8.00 (d, J = 7.2 Hz, 1H),7.81-7.88 (m, NCCD₃ 1H), 7.73-7.81 (m, 2H), 7.18-7.39 (m, 6H), 6.54 (d,J = 7.6 Hz, 1H), 2.81-2.92 (m, 2H), 2.32-2.41 (m, 2H) 246 400 MHz 9.58(d, J = 7.4 Hz, 1H), 8.89 (d, J = 3.9 Hz, 1H), 8.22-8.30 (m, d₆-DMSO2H), 8.19 (dt, J = 7.8, 1.3 Hz, 1H), 7.87 (dt, J = 7.7, 1.2 Hz, 1H),7.48-7.78 (m, 11H), 6.81 (d, J = 7.4 Hz, 1H) 247 400 MHz 9.86 (s, 1H),8.83 (s, 1H), 8.72 (d, J = 4.7 Hz, 1H), d₄-MeOH 8.64-8.70 (m, 1H),8.56-8.64 (m, 2H), 8.43 (dd, J = 8.7, 1.5 Hz, 1H), 8.16 (td, J = 7.8,1.6 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 2.2 Hz, 1H),7.61-7.67 (m, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.42 (dd, J = 8.3, 2.1 Hz,1H), 6.58 (s, 1H) 248 300 MHz 9.10 (d, J = 7.7 Hz, 1H), 8.57 (dd, J =4.7, 1.5 Hz, 1H), 8.15 (d, d₆-DMSO J = 2.5 Hz, 1H), 7.97 (dd, J = 8.1,1.4 Hz, 1H), 7.90 (dd, J = 9.6, 2.6 Hz, 1H), 7.64-7.76 (m, J = 8.3 Hz,2H), 7.48-7.62 (m, J = 8.2 Hz, 2H), 7.43 (dd, J = 8.1, 4.6 Hz, 1H), 6.77(d, J = 7.7 Hz, 1H), 6.33 (d, J = 9.6 Hz, 1H) 249 300 MHz 9.03 (d, J =7.7 Hz, 1H), 8.58 (dd, J = 4.6, 1.4 Hz, 1H), 8.50 (d, d₆-DMSO J = 2.5Hz, 1H), 7.99 (dd, J = 8.2, 1.5 Hz, 1H), 7.90 (dd, J = 9.5, 2.6 Hz, 1H),7.65-7.78 (m, J = 8.2 Hz, 2H), 7.51-7.62 (m, J = 8.2 Hz, 2H), 7.43 (dd,J = 8.2, 4.7 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 6.39 (d, J = 9.5 Hz,1H), 3.47 (s, 3H) 250 300 MHz 9.10 (d, J = 7.7 Hz, 1H), 8.38-8.50 (m,1H), 8.15 (d, J = 2.5 Hz, d₆-DMSO 1H), 7.89 (dd, J = 9.6, 2.8 Hz, 1H),7.75 (ddd, J = 10.1, 8.6, 1.2 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.61(d, J = 8.3 Hz, 1H), 7.42-7.54 (m, 1H), 7.38 (dd, J = 8.4, 2.0 Hz, 1H),6.61 (d, J = 7.9 Hz, 1H), 6.34 (d, J = 9.6 Hz, 1H) 251 300 MHz 9.05 (d,J = 7.9 Hz, 1H), 8.49 (d, J = 2.5 Hz, 1H), 8.40-8.47 (m, d₆-DMSO 1H),7.90 (dd, J = 9.5, 2.6 Hz, 1H), 7.76 (ddd, J = 10.0, 8.5, 1.3 Hz, 1H),7.69 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.47 (dt, J = 8.6,4.3 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 6.63 (d, J = 7.6 Hz, 1H),6.40 (d, J = 9.5 Hz, 1H), 3.47 (s, 3H) 252 300 MHz 8.51 (d, J = 4.8 Hz,1H), 8.44 (d, J = 7.0 Hz, 1H), 8.25 (d, J = 2.3 Hz, CDCl₃ 1H), 7.88 (dd,J = 9.5, 2.5 Hz, 1H), 7.53-7.65 (m, 1H), 7.36-7.50 (m, 3H), 7.17 (d, J =8.2 Hz, 2H), 6.78 (d, J = 9.5 Hz, 1H), 6.66 (d, J = 7.2 Hz, 1H), 3.66(s, 3H) 253 300 MHz 9.18 (s, 1H), 9.00 (d, J = 6.6 Hz, 1H), 8.52 (d, J =4.4 Hz, 1H), CDCl₃ 8.16-8.39 (m, 2H), 7.94 (d, J = 14.3 Hz, 2H),7.49-7.73 (m, 5H), 7.36-7.49 (m, 1H), 6.68 (d, J = 5.4 Hz, 1H) 254 300MHz 9.15 (s, 1H), 8.93 (d, J = 4.1 Hz, 1H), 8.77 (d, J = 7.2 Hz, 1H),CDCl₃ 8.04-8.38 (m, 3H), 7.94 (d, J = 18.1 Hz, 2H), 7.38-7.65 (m, 5H),6.86 (d, J = 7.3 Hz, 1H) 255 300 MHz 8.39-8.56 (m, 1H), 8.08-8.34 (m,2H), 7.72 (dd, J = 9.5, 2.6 Hz, CDCl₃ 1H), 7.27-7.54 (m, 4H), 7.14 (d, J= 7.9 Hz, 2H), 6.35-6.73 (m, 2H), 4.03 (dd, J = 7.2, 3.7 Hz, 2H), 1.37(t, J = 7.2 Hz, 3H) 256 300 MHz 9.09 (d, J = 3.5 Hz, 1H), 8.79 (d, J =8.2 Hz, 1H), 8.64 (s, 1H), d₄-MeOH 8.36 (d, J = 7.7 Hz, 1H), 8.19 (d, J= 9.1 Hz, 1H), 7.83 (dd, J = 8.3, 4.7 Hz, 1H), 7.70 (d, J = 8.2 Hz, 3H),7.52 (d, J = 8.2 Hz, 2H), 7.33-7.47 (m, 2H), 7.30 (d, J = 7.6 Hz, 1H),6.88 (s, 1H) 257 400 MHz 8.97 (dd, J = 4.1, 1.6 Hz, 1H), 8.43 (s, 1H),8.19-8.26 (m, 1H), CDCl₃ 8.07 (dd, J = 8.5, 1.7 Hz, 1H), 7.93 (d, J =8.6 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.60 (q, J = 7.0 Hz, 2H),7.48-7.54 (m, 2H), 7.38 (d, J = 7.8 Hz, 1H), 7.11-7.25 (m, 2H),6.83-6.93 (m, 2H) 258 300 MHz 9.03 (d, J = 7.7 Hz, 1H), 8.13 (d, J = 2.3Hz, 1H), 8.04 (dd, J = 9.6, d₄-MeOH 2.6 Hz, 1H), 7.59-7.72 (m, J = 8.2Hz, 2H), 7.46-7.54 (m, J = 8.2 Hz, 2H), 7.36-7.46 (m, 1H), 7.05 (t, J =8.4 Hz, 2H), 6.87 (d, J = 4.8 Hz, 1H), 6.53 (d, J = 9.5 Hz, 1H) 259 300MHz 9.01-9.16 (m, 2H), 8.80 (d, J = 8.3 Hz, 1H), 8.66 (s, 1H), d₄-MeOH8.36 (d, J = 9.2 Hz, 1H), 8.19 (d, J = 8.9 Hz, 1H), 7.83 (dd, J = 8.5,4.7 Hz, 1H), 7.57-7.73 (m, 4H), 6.79 (s, 1H) 260 300 MHz 9.14 (dd, J =4.8, 1.3 Hz, 1H), 8.76-8.92 (m, 3H), 8.61 (s, 1H), d₄-MeOH 8.17-8.32 (m,2H), 7.92 (dd, J = 8.4, 4.9 Hz, 1H), 7.84 (d, J = 5.1 Hz, 1H), 7.68-7.79(m, J = 8.2 Hz, 2H), 7.46-7.58 (m, J = 8.0 Hz, 2H), 6.99 (s, 1H) 261 400MHz 9.00 (dd, J = 4.2, 1.5 Hz, 1H), 8.84 (d, J = 4.7 Hz, 1H), 8.62 (s,CDCl₃ 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.21 (d, J = 7.6 Hz, 1H), 8.13 (dd,J = 8.4, 1.6 Hz, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.92 (d, J = 8.4 Hz,1H), 7.44-7.51 (m, 2H), 7.35-7.42 (m, 2H), 7.20-7.30 (m, 3H), 6.79 (d, J= 8.0 Hz, 1H) 287 400 MHz 11.99 (br. s., 1H), 9.14 (d, J = 7.8 Hz, 1H),8.44 (d, J = 4.7 Hz, DMSO-d₆ 1H), 8.16 (d, J = 2.5 Hz, 1H), 7.90 (dd, J= 9.6, 2.7 Hz, 1H), 7.73-7.80 (m, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.60(d, J = 8.0 Hz, 2H), 7.47 (dt, J = 8.5, 4.3 Hz, 1H), 6.69 (d, J = 7.8Hz, 1H), 6.33 (d, J = 9.6 Hz, 1H) 288 400 MHz 9.31 (d, J = 8.0 Hz, 1H),8.47 (t, J = 2.8 Hz, 2H), 7.37-7.42 (m, DMSO-d₆ 1H), 7.69-7.81 (m, 2H),7.45-7.65 (m, 3H), 7.26-7.32 (m, 3H), 3.65 (s, 2H) 289 400 MHz 8.54 (s,2H), 8.35-8.37 (d, J = 4.8 Hz, 1H), 7.78 (d, J = 6.8 Hz, DMSO-d₆ 1H),7.67 (d, J = 7.6 Hz, 1H), 7.37-7.42 (m, 1H), 7.28-7.32 (m, 2H),7.13-7.20 (m, 3H), 6.38 (dd, J = 6.8 Hz, 1H), 3.65 (s, 2H) 290 400 MHz9.33 (d, J = 8.4 Hz, 1H), 8.45-8.46 (m, 3H), 7.76 (m, 1H), DMSO-d₆7.50-7.55 (m, 1H), 7.46-7.48 (m, 2H), 7.25-7.28 (m, 3H), 6.47 (d, J =8.0 Hz, 1H), 3.64 (s, 2H) 291 400 MHz 12.00 (s, 1H), 9.19 (d, J = 8.0Hz, 1H), 8.19 (s, 1H), DMSO-d₆ 7.99-8.03 (m, 1H), 7.90 (dd, J = 9.6, 2.4Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.27-7.29(m, 1H), 6.65 (d, J = 7.6 Hz, 1H), 6.38 (d, J = 9.6 Hz, 1H) 292 400 MHz12.05 (br. s., 1H), 9.07 (d, J = 8.0 Hz, 1H), 8.55 (d, J = 2.8 Hz,DMSO-d₆ 1H), 8.15 (br. s., 1H), 7.91 (dd, J = 9.6, 2.4 Hz, 1H,),7.73-7.78 (m, 1H), 7.52-7.61 (m, 3H) 7.32 (d, J = 8.4 Hz, 1H), 6.43 (d,J = 8.0 Hz, 1H), 6.35 (d, J = 9.6 Hz, 1H) 293 400 MHz 12.02 (br. s.,1H), 9.05 (d, J = 8.0 Hz, 1H), 8.55 (dd, J = 4.7, 0.8 Hz, DMSO-d₆ 1H),8.16 (d, J = 2.3 Hz, 1H), 7.91 (dd, J = 9.7, 2.6 Hz, 1H), 7.82 (td, J =7.7, 1.8 Hz, 1H), 7.46-7.63 (m, 3H), 7.22-7.39 (m, 2H), 6.27-6.50 (m,2H) 294 400 MHz 8.63 (d, J = 4.7 Hz, 1H), 8.38 (d, J = 5.9 Hz, 1H), 8.14(d, J = 2.3 Hz, CDCl₃ 1H), 7.64-7.84 (m, 2H), 7.27-7.32 (m, 1H),7.16-7.25 (m, 3H), 6.60 (d, J = 9.6 Hz, 1H), 6.19 (d, J = 6.1 Hz, 1H),3.60 (s, 3H) 295 400 MHz 12.02 (br. s., 1H), 9.02 (d, J = 7.4 Hz, 1H),8.14 (br. s., 1H), DMSO-d₆ 7.90 (d, J = 9.4 Hz, 1H), 7.51-7.65 (m, 1H),7.30-7.50 (m, 3H), 7.12-7.29 (m, 3H), 6.58 (d, J = 7.4 Hz, 1H), 6.35 (d,J = 9.4 Hz, 1H) 296 400 MHz 8.15 (d, J = 2.3 Hz, 1H), 7.61 (dd, J = 9.6,2.5 Hz, 1H), CDCl₃ 7.30-7.42 (m, 2H), 6.97-7.26 (m, 5H), 6.71 (d, J =8.0 Hz, 1H), 6.55 (dd, J = 8.8, 4.1 Hz, 2H), 3.60 (s, 3H) 297 400 MHz9.08 (d, J = 6.8 Hz, 1H), 8.43 (d, J = 20.0 Hz, 2H), 7.94 (d, J = 9.2Hz, DMSO-d₆ 1H), 7.77 (br. s., 1H), 7.43-7.65 (m, 3H), 7.33 (d, J = 8.2Hz, 1H), 6.67 (d, J = 7.0 Hz, 1H), 6.40 (d, J = 8.8 Hz, 1H), 4.91 (br.s., 1H), 3.97 (br. s., 2H), 3.63 (br. s., 2H) 298 400 MHz 9.10 (d, J =7.8 Hz, 1H), 8.31-8.60 (m, 2H), 7.94 (dd, J = 9.5, DMSO-d₆ 2.6 Hz, 1H),7.77 (ddd, J = 9.9, 8.6, 1.1 Hz, 1H), 7.42-7.66 (m, 3H), 7.33 (d, J =8.4 Hz, 1H), 6.69 (d, J = 7.6 Hz, 1H), 6.39 (d, J = 9.6 Hz, 1H), 4.94(d, J = 5.3 Hz, 1H), 4.08 (dd, J = 12.9, 3.3 Hz, 1H), 3.82-3.97 (m, 1H),3.55 (dd, J = 12.8, 8.5 Hz, 1H), 1.08 (d, J = 6.5 Hz, 3H) 299 400 MHz9.07 (d, J = 7.0 Hz, 1H), 8.32-8.59 (m, 2H), 7.95 (d, J = 9.6 Hz, DMSOd₆ 1H), 7.76 (t, J = 9.1 Hz, 1H), 7.39-7.63 (m, 3H), 7.33 (d, J = 8.2Hz, 1H), 6.67 (d, J = 7.4 Hz, 1H), 6.39 (d, J = 9.4 Hz, 1H), 4.91 (br.s., 1H), 4.07 (d, J = 12.7 Hz, 1H), 3.90 (br. s., 1H), 3.59 (d, J = 10.2Hz, 1H), 1.08 (d, J = 3.5 Hz, 3H) 300 400 MHz 9.13 (d, J = 7.8 Hz, 1H),8.34-8.54 (m, 2H), 7.95 (dd, J = 9.6, DMSO-d₆ 2.7 Hz, 1H), 7.65-7.87 (m,3H), 7.60 (d, J = 8.2 Hz, 2H), 7.48 (dt, J = 8.5, 4.4 Hz, 1H), 6.72 (d,J = 7.8 Hz, 1H), 6.39 (d, J = 9.6 Hz, 1H), 4.94 (d, J = 5.3 Hz, 1H),4.07 (dd, J = 12.8, 3.2 Hz, 1H), 3.90 (td, J = 5.8, 2.5 Hz, 1H), 3.55(dd, J = 12.9, 8.4 Hz, 1H), 1.08 (d, J = 6.5 Hz, 3H) 301 400 MHz 9.09(d, J = 7.0 Hz, 1H), 8.26-8.63 (m, 2H), 7.95 (d, J = 9.4 Hz, DMSO-d₆1H), 7.67-7.82 (m, 3H), 7.60 (d, J = 7.0 Hz, 2H), 7.48 (d, J = 3.9 Hz,1H), 6.71 (d, J = 6.8 Hz, 1H), 6.39 (d, J = 9.6 Hz, 1H), 4.91 (br. s.,1H), 4.07 (d, J = 12.7 Hz, 1H), 3.90 (br. s., 1H), 3.46-3.70 (m, 1H),1.08 (d, J = 2.9 Hz, 3H) 302 400 MHz 9.08 (d, J = 7.8 Hz, 1H), 8.24-8.60(m, 2H), 7.97 (dd, J = 9.5, DMSO-d₆ 2.6 Hz, 1H), 7.76 (ddd, J = 10.0,8.6, 1.2 Hz, 1H), 7.42-7.63 (m, 3H), 7.33 (d, J = 8.6 Hz, 1H), 6.67 (d,J = 7.6 Hz, 1H), 6.41 (d, J = 9.6 Hz, 1H), 4.80 (s, 1H), 3.92 (s, 2H),1.06 (s, 6H) 303 400 MHz 9.12 (d, J = 7.8 Hz, 1H), 8.43-8.53 (m, 1H),8.39 (d, J = 2.5 Hz, DMSO-d₆ 1H), 7.98 (dd, J = 9.6, 2.7 Hz, 1H),7.68-7.84 (m, 3H), 7.60 (d, J = 8.2 Hz, 2H), 7.37-7.54 (m, 1H), 6.71 (d,J = 7.6 Hz, 1H), 6.41 (d, J = 9.6 Hz, 1H), 4.81 (s, 1H), 3.92 (s, 2H),1.06 (s, 6H) 304 400 MHz 9.30 (d, J = 7.8 Hz, 1H), 8.36-8.55 (m, 2H),7.94 (dd, J = 9.5, DMSO-d₆ 2.4 Hz, 1H), 7.68-7.84 (m, 1H), 7.44-7.65 (m,3H), 7.33 (d, J = 8.6 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 6.42 (d, J =9.6 Hz, 1H), 5.50 (t, J = 7.2 Hz, 1H), 4.57-5.03 (m, 4H) 305 400 MHz9.35 (d, J = 7.8 Hz, 1H), 8.31-8.61 (m, 2H), 7.94 (dd, J = 9.6, DMSO-d₆2.5 Hz, 1H), 7.68-7.84 (m, 3H), 7.60 (d, J = 8.2 Hz, 2H), 7.48 (dt, J =8.5, 4.4 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H), 6.42 (d, J = 9.6 Hz, 1H),5.51 (t, J = 7.2 Hz, 1H), 4.57-5.03 (m, 4H) 306 400 MHz 8.94 (dd, J =4.1, 1.4 Hz, 1H), 8.87 (d, J = 4.3 Hz, 1H), 8.53 (s, CDCl₃ 1H), 8.49 (d,J = 8.0 Hz, 1H), 8.15 (d, J = 7.8 Hz, 1H), 8.07 (dd, J = 8.4, 1.6 Hz,1H), 7.99 (d, J = 7.6 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.36-7.51 (m,4H), 7.20-7.33 (m, 3H), 6.93 (d, J = 8.0 Hz, 1H) 307 400 MHz 9.95 (s, 1H), 9.82 (br. s., 1 H), 8.47 (d, J = 4.7 Hz, 1 H), DMSO-d₆ 8.19-8.30 (m,2 H), 7.72-7.83 (m, 3 H), 7.66-7.71 (m, 2 H), 7.50 (dt, J = 8.5, 4.4 Hz,1 H), 6.78 (br. s., 1 H) 308 400 MHz 9.93 (br. s., 1 H), 9.38 (d, J =7.2 Hz, 1 H), 8.82 (s, 1 H), DMSO-d₆ 8.47 (d, J = 4.7 Hz, 1 H),7.72-7.83 (m, 4 H), 7.66-7.71 (m, 2 H), 7.50 (dt, J = 8.5, 4.4 Hz, 1 H),6.77 (br. s., 1 H) 309 400 MHz 9.95 (s, 1 H), 9.72-9.81 (m, 1 H), 8.47(d, J = 4.5 Hz, 1 H), DMSO-d₆ 8.19-8.29 (m, 2 H), 7.78 (t, J = 9.2 Hz, 1H), 7.59 (m, J = 8.6 Hz, 2 H), 7.48 (dt, J = 8.4, 4.3 Hz, 1 H), 7.37 (m,J = 8.2 Hz, 2 H), 6.69-6.75 (m, 1 H) 310 400 MHz 9.87 (d, J = 7.4 Hz, 1H), 9.38 (d, J = 7.0 Hz, 1 H), 8.81 (s, 1 H), DMSO-d₆ 8.47 (d, J = 4.5Hz, 1 H), 7.73-7.82 (m, 2 H), 7.58 (m, J = 8.6 Hz, 2 H), 7.45-7.52 (m, 1H), 7.37 (m, J = 8.2 Hz, 2 H), 6.71 (d, J = 7.4 Hz, 1 H) 311 400 MHz9.94 (s, 1 H), 9.82 (br. s., 1 H), 8.94 (d, J = 4.5 Hz, 1 H), DMSO-d₆8.18-8.31 (m, 3 H), 7.73 (d, J = 8.4 Hz, 2 H), 7.65 (dd, J = 7.8, 4.9Hz, 1 H), 7.59 (d, J = 8.2 Hz, 2 H), 6.82 (s, 1 H) 312 400 MHz 9.93 (s,1 H), 9.37 (d, J = 7.0 Hz, 1 H), 8.94 (d, J = 4.3 Hz, 1 H), DMSO-d₆ 8.80(s, 1 H), 8.28 (d, J = 7.4 Hz, 1 H), 7.78 (dd, J = 7.1, 1.5 Hz, 1 H),7.73 (m, J = 8.2 Hz, 2 H), 7.65 (dd, J = 8.0, 4.9 Hz, 1 H), 7.58 (d, J =8.2 Hz, 2 H), 6.81 (s, 1 H) 313 400 MHz 9.17 (d, J = 7.6 Hz, 1 H), 8.43(d, J = 4.3 Hz, 1 H), 7.81 (s, 1 H), DMSO-d₆ 7.75 (d, J = 8.0 Hz, 1 H),7.62-7.71 (m, 3 H), 7.59 (d, J = 8.2 Hz, 2 H), 7.27 (dd, J = 7.5, 4.8Hz, 1 H), 7.11 (d, J = 8.0 Hz, 1 H), 6.61 (d, J = 7.6 Hz, 1 H), 2.33 (s,3 H) 314 400 MHz 9.35 (d, J = 7.6 Hz, 1 H), 9.22 (s, 1 H), 8.44 (d, J =4.1 Hz, 1 H), DMSO-d₆ 8.04 (s, 1 H), 7.56-7.72 (m, 8 H), 7.28 (dd, J =7.5, 4.8 Hz, 1 H), 6.65 (d, J = 7.6 Hz, 1 H), 2.36 (s, 3 H) 315 400 MHz13.09 (br. s., 1 H), 9.58 (d, J = 7.6 Hz, 1 H), 8.42-8.52 (m, 1 H),DMSO-d₆ 8.12 (m, 2 H), 7.92 (m, 2 H), 7.72-7.83 (m, 3 H), 7.64-7.69 (m,2 H), 7.50 (dt, J = 8.5, 4.4 Hz, 1 H), 6.77 (d, J = 7.6 Hz, 1 H) 316 400MHz 13.09 (br. s., 1 H), 9.52 (d, J = 7.8 Hz, 1 H), 8.45-8.51 (m, 1 H),DMSO-d₆ 8.11 (m, 2 H), 7.92 (m, 2 H), 7.78 (ddd, J = 10.0, 8.6, 1.2 Hz,1 H), 7.57 (m, 2 H), 7.49 (dt, J = 8.5, 4.3 Hz, 1 H), 7.37 (m, 2 H),6.71 (d, J = 7.6 Hz, 1 H) 317 400 MHz 13.51 (s, 1 H), 9.22 (d, J = 7.4Hz, 1 H), 8.53 (d, J = 4.7 Hz, 1 H), DMSO-d₆ 7.76-7.85 (m, 2 H), 7.70(m, 2 H), 7.60 (m, 2 H), 7.53 (dt, J = 8.6, 4.4 Hz, 1 H), 6.98 (dd, J =9.9, 2.2 Hz, 1 H), 6.51 (d, J = 6.5 Hz, 1 H) 318 400 MHz 10.31 (s, 1 H),9.14 (d, J = 7.8 Hz, 1 H), 8.42-8.50 (m, 1 H), DMSO-d₆ 7.83 (s, 1 H),7.70-7.81 (m, 4 H), 7.63 (d, J = 8.2 Hz, 2 H), 7.49 (dt, J = 8.5, 4.4Hz, 1 H), 6.90 (d, J = 8.4 Hz, 1 H), 6.74 (d, J = 7.6 Hz, 1 H), 2.94 (t,J = 7.5 Hz, 2 H), 2.47-2.51 (m, 2H) 319 400 MHz 12.76 (br. s., 1 H),9.29 (d, J = 7.6 Hz, 1 H), 8.58 (d, J = 4.7 Hz, 1 DMSO-d₆ H), 8.06 (d, J= 1.2 Hz, 1 H), 7.99 (s, 1 H), 7.82 (ddd, J = 9.9, 8.6, 1.1 Hz, 1 H),7.72 (m, 2 H), 7.60 (m, 2 H), 7.54 (dt, J = 8.5, 4.4 Hz, 1 H), 6.55 (dd,J = 7.4, 1.4 Hz, 1 H) 320 400 MHz 8.80 (d, J = 7.6 Hz, 1 H), 8.52-8.58(m, 1 H), 7.81 (ddd, J = 10.0, DMSO-d₆ 8.5, 1.3 Hz, 1 H), 7.72 (m, 2 H),7.58 (m, 2 H), 7.53 (dt, J = 8.6, 4.4 Hz, 1 H), 6.54 (dd, J = 7.6, 1.2Hz, 1 H), 5.88 (s, 1 H), 4.27-4.37 (m, 2 H), 4.21 (t, J = 6.7 Hz, 2 H),2.16-2.28 (m, 2 H) 321 400 MHz 8.80 (d, J = 7.6 Hz, 1 H), 8.52-8.58 (m,1 H), 7.81 (ddd, J = 10.0, DMSO-d₆ 8.5, 1.3 Hz, 1 H), 7.72 (m, 2 H 7.58(m, 2 H), 7.53 (dt, J = 8.6, 4.4 Hz, 1 H), 6.54 (dd, J = 7.6, 1.2 Hz, 1H), 5.88 (s, 1 H), 4.27-4.37 (m, 2 H), 4.21 (t, J = 6.7 Hz, 2 H),2.16-2.28 (m, 2 H) 322 400 MHz 12.86 (br. s., 1 H), 8.82 (d, J = 7.6 Hz,1 H), 8.56 (d, J = 4.7 Hz, 1 DMSO-d₆ H), 7.81 (ddd, J = 9.9, 8.5, 1.2Hz, 1 H), 7.72 (m, 2 H), 7.59 (m, 2 H), 7.53 (dt, J = 8.6, 4.4 Hz, 1 H),6.54 (d, J = 7.2 Hz, 1 H), 2.61 (t, J = 5.7 Hz, 4 H), 1.61-1.77 (m, 4 H)323 400 MHz 13.08 (br. s., 1 H), 9.47 (d, J = 7.6 Hz, 1 H), 8.47 (d, J =4.1 Hz, 1 DMSO-d₆ H), 8.09 (m, 2 H), 7.90 (m, 2 H), 7.67-7.76 (m, 3 H),7.61 (d, J = 8.2 Hz, 2 H), 7.34 (dd, J = 7.5, 4.8 Hz, 1 H), 6.65 (d, J =7.4 Hz, 1 H), 2.35 (s, 3 H) 324 400 MHz 11.98 (br. s., 1 H), 8.95 (d, J= 8.0 Hz, 1 H), 8.45 (d, J = 4.5 Hz, 1 DMSO-d₆ H), 8.17 (d, J = 2.3 Hz,1 H), 7.90 (dd, J = 9.6, 2.5 Hz, 1 H), 7.70 (t, J = 9.3 Hz, 1 H), 7.43(dt, J = 8.5, 4.3 Hz, 1 H), 6.97 (s, 2 H), 6.90 (s, 1 H), 6.52 (d, J =7.8 Hz, 1 H), 6.31 (d, J = 9.6 Hz, 1 H), 2.23 (s, 6 H) 325 400 MHz 12.00(br. s., 1 H), 9.05 (d, J = 8.0 Hz, 1 H), 8.43-8.49 (m, 1 H), DMSO-d₆8.18 (d, J = 2.5 Hz, 1 H), 7.92 (dd, J = 9.6, 2.7 Hz, 1 H), 7.74 (ddd, J= 10.1, 8.5, 1.2 Hz, 1 H), 7.46 (1 dt, J = 8.5, 4.3 Hz, 1 H), 7.00-7.07(m, 2 H), 6.95 (d, J = 9.6 Hz, 1 H), 6.59 (d, J = 7.8 Hz, 1 H), 6.35 (d,J = 9.6 Hz, 1 H), 2.30 (s, 3 H) 326 400 MHz 8.98 (d, J = 8.0 Hz, 1 H),8.52 (d, J = 2.3 Hz, 1 H), 8.46 (d, J = 4.7 Hz, DMSO-d₆ 1 H), 7.91 (dd,J = 9.4, 2.5 Hz, 1 H), 7.74 (t, J = 9.3 Hz, 1 H), 7.46 (dt, J = 8.5, 4.4Hz, 1 H), 7.00-7.07 (m, 2 H), 6.95 (d, J = 9.6 Hz, 1 H), 6.60 (d, J =8.0 Hz, 1 H), 6.40 (d, J = 9.6 Hz, 1 H), 3.48 (s, 3 H), 2.29 (s, 3 H)327 400 MHz 12.01 (br. s., 1 H), 9.20 (d, J = 7.8 Hz, 1 H), 8.42-8.48(m, 1 H), DMSO-d₆ 8.17 (d, J = 2.5 Hz, 1 H), 7.91 (dd, J = 9.6, 2.7 Hz,1 H), 7.78 (ddd, J = 10.0, 8.5, 1.3 Hz, 1 H), 7.58-7.70 (m, 3 H), 7.49(dt, J = 8.5, 4.4 Hz, 1 H), 6.76 (d, J = 7.8 Hz, 1 H), 6.36 (d, J = 9.6Hz, 1 H) 328 400 MHz 9.16 (d, J = 7.8 Hz, 1 H), 8.50 (d, J = 2.3 Hz, 1H), 8.44 (d, J = 4.7 Hz, DMSO-d₆ 1 H), 7.91 (dd, J = 9.5, 2.4 Hz, 1 H),7.78 (t, J = 9.3 Hz, 1 H), 7.59-7.69 (m, 3 H), 7.49 (dt, J = 8.5, 4.3Hz, 1 H), 6.76 (d, J = 7.6 Hz, 1 H), 6.41 (d, J = 9.4 Hz, 1 H), 3.48 (s,3 H) 329 400 MHz 12.01 (br. s., 1 H), 9.10 (d, J = 8.0 Hz, 1 H), 8.45(dt, J = 4.5, 1.3 Hz, DMSO-d₆ 1 H), 8.18 (d, J = 2.5 Hz, 1 H), 7.91 (dd,J = 9.7, 2.6 Hz, 1 H), 7.77 (ddd, J = 10.1, 8.5, 1.2 Hz, 1 H), 7.49 (dt,J = 8.5, 4.3 Hz, 1 H), 7.10-7.22 (m, 3 H), 6.65 (d, J = 7.6 Hz, 1 H),6.36 (d, J = 9.6 Hz, 1 H) 330 400 MHz 9.05 (d, J = 7.8 Hz, 1 H), 8.52(d, J = 2.5 Hz, 1 H), 8.43-8.49 (m, DMSO-d₆ 1 H), 7.92 (dd, J = 9.5, 2.6Hz, 1 H), 7.78 (ddd, J = 10.0, 8.6, 1.2 Hz, 1 H), 7.49 (dt, J = 8.4, 4.4Hz, 1 H), 7.10-7.23 (m, 3 H), 6.67 (d, J = 7.6 Hz, 1 H), 6.41 (d, J =9.4 Hz, 1 H), 3.49 (s, 3 H) 331 400 MHz 12.01 (br. s., 1 H), 9.07 (d, J= 8.0 Hz, 1 H), 8.44 (d, J = 4.5 Hz, 1 DMSO-d₆ H), 8.16 (d, J = 2.5 Hz,1 H), 7.90 (dd, J = 9.6, 2.5 Hz, 1 H), 7.74 (t, J = 9.3 Hz, 1 H),7.34-7.56 (m, 3 H), 7.19-7.27 (m, 1 H), 6.61 (d, J = 7.8 Hz, 1 H), 6.34(d, J = 9.6 Hz, 1 H) 332 400 MHz 9.02 (d, J = 7.8 Hz, 1 H), 8.50 (d, J =2.5 Hz, 1 H), 8.45 (d, J = 4.5 Hz, DMSO-d₆ 1 H), 7.90 (dd, J = 9.5, 2.6Hz, 1 H), 7.75 (ddd, J = 10.0, 8.6, 1.0 Hz, 1 H), 7.35-7.56 (m, 3 H),7.19-7.28 (m, 1 H), 6.63 (d, J = 7.6 Hz, 1 H), 6.40 (d, J = 9.4 Hz, 1H), 3.48 (s, 3 H) 333 400 MHz 11.95 (br. s., 1 H), 9.15 (d, J = 8.0 Hz,1 H), 8.45 (d, J = 4.5 Hz, 1 DMSO-d₆ H), 8.16 (d, J = 2.5 Hz, 1 H), 7.90(dd, J = 9.6, 2.7 Hz, 1 H), 7.69-7.78 (m, 1 H), 7.53 (d, J = 9.6 Hz, 2H), 7.41-7.49 (m, 2 H), 6.66 (d, J = 7.8 Hz, 1 H), 6.33 (d, J = 9.6 Hz,1 H), 2.37 (s, 3 H) 334 400 MHz 11.97 (br. s., 1 H), 9.02 (d, J = 7.8Hz, 1 H), 8.43 (d, J = 4.7 Hz, 1 DMSO-d₆ H), 8.16 (d, J = 2.3 Hz, 1 H),7.90 (dd, J = 9.7, 2.6 Hz, 1 H), 7.67-7.76 (m, 1 H), 7.44 (dt, J = 8.5,4.4 Hz, 1 H), 7.19-7.26 (m, 1 H), 7.16 (d, J = 11.2 Hz, 1 H), 7.08 (d, J= 7.8 Hz, 1 H), 6.57 (d, J = 7.8 Hz, 1 H), 6.33 (d, J = 9.6 Hz, 1 H),2.19 (s, 3 H) 335 400 MHz 8.95 (d, J = 7.8 Hz, 1 H), 8.51 (d, J = 2.5Hz, 1 H), 8.44 (d, J = 4.5 Hz, DMSO-d₆ 1 H), 7.90 (dd, J = 9.5, 2.6 Hz,1 H), 7.68-7.77 (m, 1 H), 7.44 (dt, J = 8.5, 4.3 Hz, 1 H), 7.20-7.27 (m,1 H), 7.17 (d, J = 11.0 Hz, 1 H), 7.09 (d, J = 7.8 Hz, 1 H), 6.59 (d, J= 7.8 Hz, 1 H), 6.39 (d, J = 9.4 Hz, 1 H), 3.47 (s, 3 H), 2.19 (s, 3 H)336 400 MHz 11.96 (br. s., 1 H), 8.99 (d, J = 8.0 Hz, 1 H), 8.44 (d, J =4.7 Hz, 1 DMSO-d₆ H), 8.15 (d, J = 2.5 Hz, 1 H), 7.89 (dd, J = 9.7, 2.6Hz, 1 H), 7.66-7.76 (m, 1 H), 7.43 (dt, J = 8.5, 4.4 Hz, 1 H), 7.21-7.29(m, 1 H), 7.07-7.15 (m, 2 H), 6.53 (d, J = 7.8 H, 1 Hz), 6.33 (d, J =9.6 Hz, 1 H), 3.80 (s, 1 H) 337 400 MHz 8.92 (d, J = 8.0 Hz, 1 H), 8.50(d, J = 2.3 Hz, 1 H), 8.44 (d, J = 4.5 Hz, DMSO-d₆ 1 H), 7.89 (dd, J =9.6, 2.5 Hz, 1 H), 7.72 (t, J = 9.0 Hz, 1 H), 7.44 (dt, J = 8.5, 4.3 Hz,1 H), 7.22-7.29 (m, 1 H), 7.06-7.17 (m, 2 H), 6.54 (d, J = 7.8 Hz, 1 H),6.39 (d, J = 9.6 Hz, 1 H), 3.81 (s, 3 H), 3.47 (s, 3 H) 338 400 MHz11.97 (br. s., 1 H), 9.00 (d, J = 8.0 Hz, 1 H), 8.44 (d, J = 4.7 Hz, 1DMSO-d₆ H), 8.15 (d, J = 2.5 Hz, 1 H), 7.90 (dd, J = 9.7, 2.6 Hz, 1 H,7.67-7.75 (m, 1 H), 7.43 (dt, J = 8.5, 4.4 Hz, 1 H), 7.26-7.33 (m, 1 H),7.16-7.24 (m, 1 H), 7.03-7.12 (m, 1 H), 6.55 (d, J = 7.8 Hz, 1 H), 6.33(d, J = 9.6 Hz, 1 H), 2.08-2.30 (m, 3 H) 339 400 MHz 8.93 (d, J = 7.8Hz, 1 H), 8.50 (d, J = 2.5 Hz, 1 H), 8.45 (d, J = 4.5 Hz, DMSO-d₆ 1 H),7.90 (dd, J = 9.5, 2.6 Hz, 1 H), 7.67-7.76 (m, 1 H), 7.44 (dt, J = 8.4,4.4 Hz, 1 H), 7.26-7.34 (m, 1 H), 7.17-7.25 (m, 1 H), 7.09 (t, J = 9.1Hz, 1 H), 6.56 (d, J = 7.8 Hz, 1 H), 6.39 (d, J = 9.6 Hz, 1 H), 3.47 (s,3 H), 2.17-2.23 (m, 3 H) 340 400 MHz 11.94 (br. s., 1 H), 9.03 (d, J =7.8 Hz, 1 H), 8.44 (d, J = 4.7 Hz, 1 DMSO-d₆ H), 8.16 (d, J = 2.5 Hz, 1H), 7.89 (dd, J = 9.6, 2.5 Hz, 1 H), 7.67-7.76 (m, 1 H), 7.36-7.48 (m, 3H), 7.16 (t, J = 8.8 Hz, 2 H), 6.59 (d, J = 7.8 Hz, 1 H), 6.32 (d, J =9.6 Hz, 1 H) 341 400 MHz 8.97 (d, J = 8.0 Hz, 1 H), 8.50 (d, J = 2.5 Hz,1 H), 8.45 (d, J = 4.7 Hz, DMSO-d₆ 1 H), 7.90 (dd, J = 9.5, 2.6 Hz, 1H), 7.73 (ddd, J = 10.0, 8.6, 1.2 Hz, 1 H), 7.38-7.49 (m, 3 H),7.12-7.21 (m, 2 H), 6.61 (d, J = 7.8 Hz, 1 H), 6.39 (d, J = 9.4 Hz, 1H), 3.47 (s, 3 H) 342 400 MHz 11.96 (br. s., 1 H), 8.97 (d, J = 7.8 Hz,1 H), 8.43 (d, J = 4.7 Hz, 1 DMSO-d₆ H), 8.15 (d, J = 2.5 Hz, 1 H), 7.90(dd, J = 9.7, 2.6 Hz, 1 H), 7.64-7.73 (m, 1 H), 7.41 (dt, J = 8.4, 4.4Hz, 1 H), 7.28 (m, 2 H), 6.88 (m, 2 H), 6.52 (d, J = 7.6 Hz, 1 H), 6.32(d, J = 9.6 Hz, 1 H), 3.72 (s, 3 H) 343 400 MHz 8.88 (d, J = 7.8 Hz, 1H), 8.48-8.53 (m, 1 H), 8.44 (d, J = 4.3 Hz, DMSO-d₆ 1 H), 7.90 (dd, J =9.5, 2.2 Hz, 1 H), 7.70 (t, J = 9.2 Hz, 1 H), 7.42 (dt, J = 8.3, 4.3 Hz,1 H), 7.29 (m, 2 H), 6.89 (m, 2 H), 6.54 (d, J = 7.6 Hz, 1 H), 6.38 (d,J = 9.4 Hz, 1 H), 3.72 (s, 3 H), 3.47 (s, 3 H) 344 400 MHz 12.00 (br.s., 1 H), 9.08 (d, J = 7.8 Hz, 1 H), 8.43 (d, J = 4.7 Hz, 1 DMSO-d₆ H),8.15 (d, J = 2.3 Hz, 1 H), 7.89 (dd, J = 9.6, 2.7 Hz, 1 H), 7.75 (ddd, J= 10.0, 8.6, 1.2 Hz, 1 H), 7.55 (t, J = 8.0 Hz, 1 H), 7.42-7.50 (m, 2H), 7.21-7.27 (m, 1 H), 6.62 (d, J = 7.8 Hz, 1 H), 6.33 (d, J = 9.8 Hz,1 H) 345 400 MHz 9.03 (d, J = 7.8 Hz, 1 H), 8.49 (d, J = 2.5 Hz, 1 H),8.44 (d, J = 4.5 Hz, DMSO-d₆ 1 H), 7.89 (dd, J = 9.6, 2.7 Hz, 1 H), 7.75(ddd, J = 10.0, 8.6, 1.2 Hz, 1 H), 7.56 (t, J = 8.0 Hz, 1 H), 7.43-7.51(m, 2 H), 7.25 (dd, J = 8.2, 1.6 Hz, 1 H), 6.64 (d, J = 7.8 Hz, 1 H),6.39 (d, J = 9.4 Hz, 1 H), 3.47 (s, 3 H) 346 400 MHz 10.65 (br. s., 1H), 9.14 (d, J = 7.8 Hz, 1 H), 8.37-8.54 (m, 1 H), DMSO-d₆ 7.81-7.86 (m,2 H), 7.77 ddd, J = 10.0, 8.6, 1.2 Hz, 1 H), 7.53-7.63 (m, 2 H), 7.49(dt, J = 8.5, 4.4 Hz, 1 H), 7.37 (d, J = 8.4 Hz, 1 H), 6.88 (d, J = 8.0Hz, 1 H), 6.70 (d, J = 7.6 Hz, 1 H), 3.55 (s, 2 H) 347 400 MHz 11.96(br. s., 1 H), 9.01 (d, J = 8.0 Hz, 1 H), 8.39-8.43 (m, 1 H), DMSO-d₆8.14 (d, J = 2.5 Hz, 1 H), 7.89 (dd, J = 9.6, 2.7 Hz, 1 H), 7.63 (d, J =6.8 Hz, 1 H), 7.46-7.54 (m, 2 H), 7.23-7.32 (m, 2 H), 6.55 (d, J = 7.8Hz, 1 H), 6.32 (d, J = 9.6 Hz, 1 H), 2.35 s, 3 H) 348 400 MHz 8.96 (d, J= 7.8 Hz, 1 H), 8.49 (d, J = 2.5 Hz, 1 H), 8.38-8.45 (m, DMSO-d₆ 1 H),7.89 (dd, J = 9.5, 2.6 Hz, 1 H), 7.61-7.67 (m, 1 H), 7.47-7.55 (m, 2 H),7.22-7.33 (m, 2 H), 6.56 (d, J = 7.8 Hz, 1 H), 6.38 (d, J = 9.6 Hz, 1H), 3.46 (s, 3 H), 2.36 (s, 3 H) 349 400 MHz 13.38-13.60 (m, 1 H), 9.22(d, J = 7.2 Hz, 1 H), 8.52 (d, J = 4.7 Hz, DMSO-d₆ 1 H), 7.75-7.86 (m, 2H), 7.48-7.58 (m, 3 H), 7.33 (d, J = 8.6 Hz, 1 H), 6.98 (dd, J = 9.9,2.2 Hz, 1 H), 6.47-6.52 (m, 1 H) 350 400 MHz 13.38-13.60 (m, 1 H), 9.17(d, J = 7.4 Hz, 1 H), 8.53 (d, J = 4.7 Hz, DMSO-d₆ 1 H), 7.75-7.85 (m, 2H), 7.46-7.56 (m, 3 H), 7.33 (d, J = 8.0 Hz, 2 H), 6.98 (dd, J = 9.9,2.1 Hz, 1 H), 6.47 (dd, J = 7.3, 1.5 Hz, 1 H) 351 400 MHz 10.29 (s, 1H), 9.12 (d, J = 7.8 Hz, 1 H), 8.44 (d, J = 4.7 Hz, 1 H), DMSO-d₆7.70-7.83 (m, 3 H), 7.50-7.62 (m, 2 H), 7.47 (dt, J = 8.5, 4.4 Hz, 1 H),7.35 (d, J = 8.4 Hz, 1 H), 6.89 (d, J = 8.2 Hz, 1 H), 6.69 (d, J = 7.8Hz, 1 H), 2.92 (t, J = 7.5 Hz, 2 H), 2.44-2.50 (m, 2 H) 352 400 MHz10.29 (1 H, s, 1 H), 9.07 (1 H, d, J = 7.8 Hz, 1 H), 8.45 (1 H, d,DMSO-d₆ J = 4.7 Hz, 1 H), 7.67-7.84 (3 H, m, 3 H), 7.52 (2 H, m, 2 H),7.46 (1 H, dt, J = 8.5, 4.4 Hz, 1 H), 7.34 (2 H, m, 2 H), 6.88 (1 H, d,J = 8.4 Hz, 1 H), 6.67 (1 H, d, J = 7.6 Hz, 1 H), 2.91 (2 H, t, J = 7.5Hz, 2 H), 2.44-2.49 (2 H, m, 2 H) 353 400 MHz 12.78 (br. s., 1 H), 9.25(d, J = 7.4 Hz, 1 H), 8.55 (d, J = 4.7 Hz, 1 DMSO-d₆ H), 8.02-8.07 (m, 1H), 7.97 (br. s., 1 H), 7.76-7.84 (m, 1 H), 7.46-7.57 (m, 3 H), 7.30 (d,J = 8.4 Hz, 1 H), 6.49 (dd, J = 7.4, 1.4 Hz, 1 H) 354 400 MHz 12.78 (br.s., 1 H), 9.23 (d, J = 7.6 Hz, 1 H), 8.55 (d, J = 4.7 Hz, 1 DMSO-d₆ H),8.05 (d, J = 1.2 Hz, 1 H), 7.97 (s, 1 H), 7.79 (ddd, J = 9.9, 8.6, 1.1Hz, 1 H), 7.44-7.56 (m, 3 H), 7.32 (d, J = 8.0 Hz, 2 H), 6.48 (dd, J =7.6, 1.6 Hz, 1 H) 355 400 MHz 8.79 (1 H, d, J = 7.6 Hz, 1 H), 8.52 (1 H,d, J = 4.7 Hz, 1 H), DMSO-d₆ 7.74-7.84 (1 H, m, 1 H), 7.44-7.58 (3 H, m,3 H), 7.29 (1 H, d, J = 8.6 Hz 1 H), 6.50 (1 H, dd, J = 7.6, 1.2 Hz, 1H), 5.87 (1 H, s, 1 H), 4.28-4.33 (2 H, m, 2 H), 4.18 (2 H, t, J = 6.4Hz, 2 H), 2.16-2.25 (m, 1 H) 356 400 MHz 8.72 (1 H, d, J = 7.8 Hz, 1 H),8.53 (1 H, d, J = 4.7 Hz, 1 H), DMSO-d₆ 7.69-7.85 (1 H, m, 1 H),7.44-7.54 (3 H, m, 3 H), 7.33 (2 H, d, J = 8.2 Hz 2 H), 6.44-6.52 (1 H,m, 1 H), 5.86 (1 H, s, 1 H), 4.28-4.33 (2 H, m, 2 H), 4.19 (2 H, t, J =6.3 Hz, 2 H), 2.16-2.25 (2 H, m, 2 H) 357 400 MHz 10.92 (s, 1 H), 9.11(d, J = 7.6 Hz, 1 H), 8.44 (d, J = 3.7 Hz, 1 H), DMSO-d₆ 7.67 (d, J =7.6 Hz, 1 H), 7.45-7.59 (m, 4 H), 7.26-7.34 (m, 2 H), 6.93 (d, J = 8.0Hz, 1 H), 6.56 (d, J = 7.6 Hz, 1 H), 4.61 (s, 2 H), 2.34 (s, 3 H) 358400 MHz 11.83 (s, 1 H), 9.27 (d, J = 7.6 Hz, 1 H), 8.44 (d, J = 3.7 Hz,1 H), DMSO-d₆ 7.66-7.74 (m, 2 H), 7.63 (d, J = 1.6 Hz, 1 H), 7.47-7.58(m, 2 H), 7.26-7.39 (m, 3 H), 6.59 (d, J = 7.8 Hz, 1 H), 2.35 (s, 3 H)359 300 MHz 11.92 (br. s., 1 H), 9.01 (d, J = 7.7 Hz, 1 H), 8.39-8.46(m, 1 H), DMSO-d₆ 8.14 (d, J = 2.5 Hz, 1 H), 7.90 (dd, J = 9.6, 2.6 Hz,1 H), 7.57-7.66 (m, 1 H), 7.46 (d, J = 8.8 Hz, 2 H), 7.21-7.35 (m, 3 H),6.53 (d, J = 7.9 Hz, 1 H), 6.32 (d, J = 9.6 Hz, 1 H), 2.31 (s, 3 H) 360300 MHz 8.94 (d, J = 7.9 Hz, 1 H), 8.50 (d, J = 2.3 Hz, 1 H), 8.44 (d, J= 3.8 Hz, DMSO-d₆ 1 H), 7.89 (dd, J = 9.5, 2.5 Hz, 1 H), 7.63 (d, J =7.0 Hz, 1 H), 7.47 (d, J = 8.6 Hz, 2 H), 7.21-7.36 (m, 3 H), 6.55 (d, J= 7.9 Hz, 1 H), 6.39 (d, J = 9.4 Hz, 1 H), 3.47 (s, 3 H), 2.33 (s, 3 H)361 400 MHz 9.35 (d, J = 8.0 Hz, 1 H), 8.57 (d, J = 4.1 Hz, 1 H), 7.83(td, J = 7.7, DMSO-d₆ 1.7 Hz, 1 H), 7.68-7.75 (m, 3 H), 7.61-7.67 (m, 3H), 7.54 (d, J = 7.8 Hz, 1 H), 7.29-7.40 (m, 2 H), 6.51 (d, J = 8.0 Hz,1 H) 362 400 MHz 10.84-12.61 (m, 1 H), 9.30 (d, J = 8.2 Hz, 1 H), 8.57(d, J = 4.3 Hz, DMSO-d₆ 1 H), 7.83 (td, J = 7.7, 1.8 Hz, 1 H), 7.71 (dd,J = 8.2, 1.6 Hz, 1 H), 7.62-7.66 (m, 1 H), 7.53 (d, J = 8.4 Hz, 3 H),7.28-7.38 (m, 4 H), 6.46 (d, J = 8.2 Hz, 1 H) 363 300 MHz 13.05 (br. s.,1H), 8.45-8.87 (m, 2H), 8.09 (d, J = 2.5 Hz, 1H), CDCl₃ 7.94 (dd, J =9.6, 2.6 Hz, 1H), 7.81 (dd, J = 7.9, 1.5 Hz, 1H), 7.40-7.63 (m, 4H),7.32 (dd, J = 7.7, 4.8 Hz, 1H), 6.92 (dd, J = 17.2, 11.0 Hz, 1H),6.44-6.71 (m, 2H), 5.65 (d, J = 17.2 Hz, 1H), 5.44 (d, J = 11.3 Hz, 1H)364 300 MHz 8.47 (d, J = 4.5 Hz, 1H), 8.32 (d, J = 6.6 Hz, 1H), 8.15 (d,J = 2.6 Hz, CDCl₃ 1H), 7.73 (dd, J = 9.5, 2.6 Hz, 1H), 7.56 (s, 4H),7.39-7.48 (m, 1H), 7.29-7.38 (m, 1H), 6.44-6.65 (m, 2H), 4.02 (qd, J =7.1, 4.2 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H) 365 300 MHz 8.46 (dt, J =4.6, 1.2 Hz, 1H), 8.26 (d, J = 6.7 Hz, 1H), 8.15 (d, J = 2.5 Hz, CDCl₃1H), 7.72 (dd, J = 9.6, 2.7 Hz, 1H), 7.27-7.58 (m, 5H), 6.58 (d, J = 9.5Hz, 1H), 6.47 (dd, J = 6.7, 2.0 Hz, 1H), 3.91-4.10 (m, 2H), 1.38 (t, J =7.2 Hz, 3H) 366 300 MHz 8.47 (d, J = 4.7 Hz, 1H), 8.26 (d, J = 6.6 Hz,1H), 8.16 (d, J = 2.5 Hz, CDCl₃ 1H), 7.72 (dd, J = 9.5, 2.6 Hz, 1H),7.41-7.52 (m, 1H), 7.31-7.40 (m, 1H), 7.16-7.27 (m, 3H), 6.37-6.64 (m,2H), 4.04 (qd, J = 7.2, 4.0 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H) 367 300MHz 8.47 (d, J = 4.7 Hz, 1H), 8.35 (d, J = 6.6 Hz, 1H), 8.22 (d, J = 2.3Hz, CDCl₃ 1H), 7.70 (dd, J = 9.5, 2.6 Hz, 1H), 7.56 (s, 4H), 7.39-7.48(m, 1H), 7.28-7.39 (m, 1H), 6.34-6.67 (m, 2H), 5.11-5.34 (m, 1H), 1.37(dd, J = 6.7, 4.2 Hz, 6H) 368 300 MHz 13.23 (br. s., 1H), 8.50 (d, J =4.5 Hz, 1H), 8.30-8.42 (m, 2H), CDCl₃ 8.18 (d, J = 2.2 Hz, 1H),7.50-7.67 (m, 4H), 7.31-7.49 (m, 2H), 6.57 (dd, J = 6.6, 1.8 Hz, 1H) 369300 MHz 11.69 (dd, J = 13.2, 6.9 Hz, 1H), 8.55 (d, J = 4.7 Hz, 1H),CDCl₃ 7.60-7.70 (m, 2H), 7.53-7.59 (m, 2H), 7.40-7.50 (m, 2H), 7.29-7.38(m, 1H), 6.91 (d, J = 9.8 Hz, 1H), 6.07 (d, J = 6.7 Hz, 1H), 5.84 (d, J= 9.6 Hz, 1H), 4.03 (s, 3H) 370 400 MHz 9.12 (d, J = 7.8 Hz, 1H),8.35-8.51 (m, 2H), 7.94 (dd, J = 9.5, d₆-DMSO 2.6 Hz, 1H), 7.66-7.84 (m,3H), 7.60 (d, J = 8.2 Hz, 2H), 7.36-7.54 (m, 1H), 6.71 (d, J = 7.8 Hz,1H), 6.40 (d, J = 9.6 Hz, 1H), 4.91 (t, J = 5.5 Hz, 1H), 3.85-4.27 (m,2H), 3.63 (q, J = 5.5 Hz, 2H) 371 300 MHz 8.36-8.52 (m, 1H), 8.30 (d, J= 6.6 Hz, 1H), 8.16 (d, J = 2.5 Hz, CDCl₃ 1H), 7.73 (dd, J = 9.6, 2.6Hz, 1H), 7.53 (s, 4H), 7.27-7.47 (m, 7H), 6.62 (d, J = 9.5 Hz, 1H), 6.54(dd, J = 6.7, 1.9 Hz, 1H), 5.15 (d, J = 3.7 Hz, 2H) 372 300 MHz8.41-8.51 (m, 1H), 8.35 (d, J = 6.7 Hz, 1H), 8.10 (d, J = 2.3 Hz, CDCl₃1H), 7.77 (dd, J = 9.7, 2.6 Hz, 1H), 7.49-7.65 (m, 5H), 7.39-7.48 (m,1H), 7.30-7.39 (m, 1H), 6.66 (d, J = 9.6 Hz, 1H), 6.57 (dd, J = 6.7, 2.0Hz, 1H), 4.64 (q, J = 8.5 Hz, 2H) 373 300 MHz 12.78 (br. s., 1H), 8.48(d, J = 4.7 Hz, 1H), 8.27 (d, J = 6.7 Hz, CDCl₃ 1H), 8.02 (d, J = 2.3Hz, 1H), 7.80 (d, J = 1.0 Hz, 1H), 7.55 (s, 4H), 7.39-7.49 (m, 1H),7.29-7.39 (m, 1H), 6.60 (dd, J = 6.8, 2.0 Hz, 1H), 2.22 (s, 3H) 374 300MHz 8.45 (d, J = 3.4 Hz, 1H), 8.28 (d, J = 5.8 Hz, 1H), 7.64 (d, J = 2.3Hz, CDCl₃ 1H), 7.21-7.56 (m, 5H), 6.97-7.20 (m, 3H), 6.61 (d, J = 6.4Hz, 1H) 375 300 MHz 8.47 (br. s., 1H), 8.32 (br. s., 1H), 7.21-7.88 (m,8H), 7.10 (br. CDCl₃ s., 1H), 6.63 (d, J = 5.7 Hz, 1H) 376 300 MHz 11.97(br. s., 1H), 9.02 (d, J = 7.7 Hz, 1H), 8.90 (d, J = 3.7 Hz, d₆-DMSO1H), 8.22 (d, J = 8.2 Hz, 1H), 8.13 (br. s., 1H), 7.88 (dd, J = 9.6, 2.8Hz, 1H), 7.65-7.75 (m, J = 8.3 Hz, 2H), 7.60 (dd, J = 7.8, 4.6 Hz, 1H),6.99-7.14 (m, J = 8.3 Hz, 2H), 6.61 (d, J = 7.3 Hz, 1H), 6.31 (d, J =9.4 Hz, 1H) 377 300 MHz 9.03 (d, J = 8.2 Hz, 1H), 8.55 (dd, J = 4.8, 0.9Hz, 1H), 8.16 (d, d₆-DMSO J = 2.5 Hz, 1H), 7.91 (dd, J = 9.6, 2.7 Hz,1H), 7.81 (td, J = 7.7, 1.9 Hz, 1H), 7.42-7.56 (m, 3H), 7.24-7.40 (m,3H), 6.39 (d, J = 8.2 Hz, 1H), 6.33 (d, J = 9.6 Hz, 1H) 378 300 MHz 9.00(d, J = 8.0 Hz, 1H), 8.57 (dd, J = 4.9, 0.8 Hz, 1H), 8.50 (d, d₆-DMSO J= 2.6 Hz, 1H), 7.92 (dd, J = 9.5, 2.6 Hz, 1H), 7.84 (td, J = 7.7, 1.8Hz, 1H), 7.44-7.57 (m, 3H), 7.28-7.40 (m, 3H), 6.33-6.49 (m, 2H) 379 300MHz 8.39-8.50 (m, 1H), 8.13 (d, J = 2.6 Hz, 1H), 8.04 (dd, J = 9.5,d₄-MeOH 2.6 Hz, 1H), 7.54-7.66 (m, 1H), 7.41 (dt, J = 8.6, 4.4 Hz, 1H),7.20-7.31 (m, J = 8.2 Hz, 2H), 7.09-7.20 (m, J = 8.0 Hz, 2H), 6.59 (s,1H), 6.53 (d, J = 9.5 Hz, 1H), 2.30 (s, 3H) 380 300 MHz 8.44 (d, J = 4.7Hz, 1H), 8.13 (d, J = 2.6 Hz, 1H), 8.04 (dd, J = 9.6, d₄-MeOH 2.7 Hz,1H), 7.58 (ddd, J = 9.9, 8.5, 1.2 Hz, 1H), 7.40 (dt, J = 8.6, 4.3 Hz,1H), 7.13 (s, 1H), 7.01-7.11 (m, 2H), 6.47-6.59 (m, 2H), 2.22 (s, 6H)381 300 MHz 8.46 (dt, J = 4.8, 1.2 Hz, 1H), 8.10-8.18 (m, 1H), 8.04 (dd,d₄-MeOH J = 9.6, 2.7 Hz, 1H), 7.60 (ddd, J = 9.9, 8.4, 1.3 Hz, 1H), 7.42(dt, J = 8.5, 4.4 Hz, 1H), 7.34-7.38 (m, 1H), 7.29 (dd, J = 8.6, 2.0 Hz,1H), 7.20 (dd, J = 8.5, 1.3 Hz, 1H), 6.58-6.65 (m, 1H), 6.53 (dd, J =9.6, 0.6 Hz, 1H), 2.28 (s, 3H) 382 300 MHz 8.57-8.68 (m, 1H), 8.13 (d, J= 2.5 Hz, 1H), 7.97-8.09 (m, d₄-MeOH 2H), 7.23-7.44 (m, 4H), 6.77 (s,1H), 6.53 (d, J = 9.6 Hz, 1H) 383 300 MHz 8.90 (d, J = 4.1 Hz, 1H),8.13-8.23 (m, 1H), 8.11 (d, J = 2.2 Hz, d₄-MeOH 1H), 8.01 (dd, J = 9.6,2.7 Hz, 1H), 7.57 (dd, J = 7.7, 5.1 Hz, 1H), 7.30-7.42 (m, 2H),7.19-7.30 (m, 1H), 6.80 (s, 1H), 6.51 (d, J = 9.6 Hz, 1H) 384 300 MHz8.65 (br. s., 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 8.0 Hz,d₄-MeOH 1H), 7.59 (br. s., 1H), 7.19-7.48 (m, 5H), 6.81 (s, 1H) 385 300MHz 8.92 (br. s., 1H), 8.20 (d, J = 6.3 Hz, 1H), 7.66 (d, J = 7.5 Hz,d₄-MeOH 1H), 7.57 (br. s., 2H), 7.36 (br. s., 2H), 7.28 (br. s., 2H),6.84 (br. s., 1H) 386 300 MHz 8.43 (dt, J = 4.6, 1.3 Hz, 1H), 8.10-8.19(m, 1H), 8.04 (dd, J = 9.6, d₄-MeOH 2.7 Hz, 1H), 7.57-7.70 (m, 1H),7.38-7.54 (m, 2H), 7.06-7.18 (m, 2H), 6.91 (s, 1H), 6.48-6.59 (m, 1H)387 300 MHz 8.45-8.57 (m, 1H), 7.64 (ddd, J = 9.8, 8.4, 1.2 Hz, 1H),d₄-MeOH 7.31-7.52 (m, 5H), 7.28 (d, J = 1.2 Hz, 1H), 6.59 (s, 1H), 4.03(s, 3H) 388 300 MHz 8.46-8.58 (m, 1H), 7.64 (ddd, J = 9.8, 8.5, 1.3 Hz,1H), d₄-MeOH 7.29-7.53 (m, 4H), 7.22 (s, 1H), 6.62 (s, 1H), 2.27-2.42(m, 3H) 389 300 MHz 8.53 (d, J = 4.7 Hz, 1H), 8.22 (d, J = 2.6 Hz, 1H),7.98 (d, J = 8.6 Hz, d₄-MeOH 1H), 7.64 (td, J = 9.1, 1.2 Hz, 1H),7.26-7.51 (m, 6H), 6.53-6.64 (m, 1H) 390 300 MHz 8.47-8.52 (m, 1H), 7.95(d, J = 8.9 Hz, 1H), 7.64 (ddd, J = 9.8, d₄-MeOH 8.5, 1.3 Hz, 1H),7.30-7.48 (m, 7H), 6.63-6.66 (m, 1H), 2.20 (s, 3H) 391 400 MHz 9.21 (d,J = 8.0 Hz, 1H), 8.52-8.63 (m, 1H), 7.73-7.93 (m, d₆₋DMSO 3H), 7.50-7.65(m, 3H), 7.40 (d, J = 8.6 Hz, 1H), 7.34 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H),7.16 (s, 1H), 6.49 (d, J = 8.0 Hz, 1H) 392 400 MHz 12.67 (br. s., 1H),9.31 (d, J = 7.8 Hz, 1H), 8.46 (d, J = 4.5 Hz, d₆₋DMSO 1H), 8.34 (s,1H), 8.25 (br. s., 1H), 7.74-7.83 (m, 2H), 7.70-7.74 (m, 2H), 7.58-7.68(m, 3H), 7.48 (dt, J = 8.5, 4.4 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H) 393400 MHz 12.70 (br. s., 1H), 9.28 (d, J = 7.0 Hz, 1H), 8.58 (d, J = 4.3Hz, d₆₋DMSO 1H), 8.09-8.46 (m, 2H), 7.76-7.92 (m, 2H), 7.49-7.75 (m,4H), 7.42 (d, J = 8.6 Hz, 1H), 7.34 (dd, J = 7.1, 5.2 Hz, 1H), 6.52 (d,J = 8.2 Hz, 1H) 394 400 MHz 9.33 (d, J = 7.8 Hz, 1H), 8.46 (d, J = 4.7Hz, 1H), 8.33 (s, 2H), d₆₋DMSO 7.88 (dd, J = 8.6, 1.4 Hz, 1H), 7.70-7.82(m, 3H), 7.61-7.69 (m, 3H), 7.48 (dt, J = 8.4, 4.4 Hz, 1H), 6.77 (d, J =7.4 Hz, 1H), 3.87 (s, 3H) 395 400 MHz 9.33 (d, J = 7.8 Hz, 1H), 8.47 (d,J = 4.7 Hz, 1H), 8.24-8.35 (m, d₆₋DMSO 2H), 7.63-7.88 (m, 7H), 7.49 (dt,J = 8.5, 4.4 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 3.90 (s, 3H) 396 400 MHz9.52 (d, J = 7.8 Hz, 1H), 8.60 (d, J = 2.3 Hz, 1H), 8.46 (d, J = 4.5 Hz,d₆₋DMSO 1H), 7.97-8.04 (m, 1H), 7.70-7.91 (m, 4H), 7.62 (d, J = 8.0 Hz,2H), 7.49 (dt, J = 8.5, 4.4 Hz, 1H), 6.72 (d, J = 7.4 Hz, 1H), 6.58 (d,J = 9.8 Hz, 1H) 397 400 MHz 12.45 (br. s., 1H), 9.27 (d, J = 7.6 Hz,1H), 8.43-8.54 (m, 1H), d₆₋DMSO 8.11 (s, 1H), 7.71-7.85 (m, 4H),7.63-7.70 (m, 2H), 7.45-7.54 (m, 2H), 6.78 (d, J = 7.6 Hz, 1H), 2.53 (s,3H) 398 400 MHz 9.87 (d, J = 7.4 Hz, 1H), 9.21 (dd, J = 2.0, 0.8 Hz,1H), d₆₋DMSO 8.56-8.63 (m, 1H), 8.52 (dd, J = 8.1, 2.1 Hz, 1H), 8.20(dd, J = 8.1, 0.7 Hz, 1H), 7.79-7.89 (m, 1H), 7.52-7.63 (m, 3H), 7.37(d, J = 8.6 Hz, 1H), 6.59 (dd, J = 7.4, 1.4 Hz, 1H), 3.95 (s, 3H) 399400 MHz 9.46 (d, J = 7.6 Hz, 1H), 8.58 (d, J = 2.3 Hz, 1H), 8.46 (d, J =4.5 Hz, d₆₋DMSO 1H), 7.97-8.06 (m, 1H), 7.88 (s, 0H), 7.72-7.83 (m, 1H),7.53-7.64 (m, 2H), 7.49 (dt, J = 8.5, 4.4 Hz, 1H), 7.34 (d, J = 8.4 Hz,1H), 6.68 (d, J = 7.6 Hz, 1H), 6.58 (d, J = 9.8 Hz, 1H) 400 400 MHz 8.51(d, J = 4.5 Hz, 1H), 8.05 (s, 1H), 7.88 (d, J = 11.2 Hz, 1H), d₄-MeOH7.66 (t, J = 9.1 Hz, 1H), 7.38-7.53 (m, 3H), 7.28-7.37 (m, 1H), 6.68 (s,1H) 401 400 MHz 8.49 (br. s., 1H), 8.26 (br. s., 1H), 8.14 (br. s., 1H),7.64 (t, J = 8.4 Hz, d₄-MeOH 1H), 7.36-7.52 (m, 3H), 7.27-7.35 (m, 1H),6.67 (br. s., 1H) 402 400 MHz 12.78 (br. s., 1H), 9.36 (d, J = 7.0 Hz,1H), 8.29-8.53 (m, 3H), d₆₋DMSO 7.77 (t, J = 9.2 Hz, 1H), 7.43-7.64 (m,3H), 7.33 (d, J = 8.2 Hz, 1H), 6.68 (d, J = 6.7 Hz, 1H) 403 400 MHz11.92 (br. s., 1H), 9.06 (d, J = 7.8 Hz, 1H), 8.44 (d, J = 4.7 Hz,d₆₋DMSO 1H), 8.03 (d, J = 2.2 Hz, 1H), 7.82 (d, J = 1.2 Hz, 1H), 7.76(ddd, J = 10.0, 8.6, 1.2 Hz, 1H), 7.51-7.63 (m, 2H), 7.48 (dt, J = 8.4,4.4 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 1.99(s, 3H) 404 400 MHz 11.09-11.51 (s, 1H), 9.80 (d, J = 7.2 Hz, 1H), 8.50(d, J = 4.5 Hz, d₆₋DMSO 1H), 7.79-7.88 (m, 1H), 7.44-7.62 (m, 3H), 7.31(d, J = 8.4 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1H), 6.60 (d, J = 6.3 Hz, 1H),6.55 (d, J = 7.2 Hz, 1H), 3.40-3.61 (s, 3H) 405 400 MHz 12.00 (br. s.,1H), 9.15 (d, J = 7.8 Hz, 1H), 8.43 (dt, J = 4.7, 1.4 Hz, d₆₋DMSO 1H),8.16 (d, J = 2.3 Hz, 1H), 7.89 (dd, J = 9.6, 2.7 Hz, 1H), 7.70-7.81 (m,2H), 7.57 (d, J = 11.9 Hz, 1H), 7.48 (dt, J = 8.5, 4.4 Hz, 1H), 7.42 (d,J = 8.2 Hz, 1H), 6.70 (d, J = 7.8 Hz, 1H), 6.34 (d, J = 9.6 Hz, 1H) 406400 MHz 9.88 (d, J = 7.6 Hz, 1H), 9.20 (dd, J = 2.0, 0.8 Hz, 1H), 8.65(d, d₆₋DMSO J = 3.9 Hz, 1H), 8.50 (dd, J = 8.0, 2.2 Hz, 1H), 8.18 (dd, J= 8.0, 0.8 Hz, 1H), 7.85 (td, J = 7.7, 1.9 Hz, 1H), 7.59-7.67 (m, 2H),7.48-7.58 (m, 1H), 7.32-7.44 (m, 2H), 6.43 (d, J = 7.6 Hz, 1H), 3.93 (s,3H) 407 400 MHz 9.12 (d, J = 7.6 Hz, 1H), 8.45 (d, J = 2.5 Hz, 2H), 7.98(dd, J = 9.5, DMSO-d₆ 2.4 Hz, 1H), 7.77 (t, J = 9.1 Hz, 1H), 7.51-7.63(m, 2H), 7.48 (dt, J = 8.5, 4.3 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 6.67(d, J = 7.6 Hz, 1H), 6.41 (d, J = 9.4 Hz, 1H), 5.63 (s, 1H), 4.03 (s,2H), 0.67-0.78 (m, 2H), 0.61 (br. s., 2H) 408 400 MHz 9.12 (dd, J =10.3, 8.1 Hz, 1H), 8.35-8.61 (m, 2H), 7.99 (dd, J = 9.6, DMSO-d₆ 1.4 Hz,1H), 7.68-7.85 (m, 1H), 7.42-7.65 (m, 3H), 7.33 (d, J = 8.6 Hz, 1H),6.61-6.82 (m, 2H), 6.46 (d, J = 9.4 Hz, 1H), 4.17-4.51 (m, 2H),3.58-3.94 (m, 1H) 409 400 MHz 8.95-9.32 (m, 1H), 8.33-8.55 (m, 2H),7.94-8.09 (m, 1H), DMSO-d₆ 7.71-7.84 (m, 1H), 7.52-7.64 (m, 2H),7.42-7.55 (m, 1H), 7.33 (d, J = 8.4 Hz, 1H), 6.63-6.82 (m, 2H), 6.46 (d,J = 9.6 Hz, 1H), 4.22-4.52 (m, 2H), 3.69-3.87 (m, 1H) 410 400 MHz 12.00(s, 1H), 9.10 (d, J = 7.6 Hz, 1H), 8.16 (s, 1H), 7.91 (dd, J = 10,DMSO-d₆ 2.8 Hz, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.64-7.56 (m, 3H),6.30-6.27 (m, 1H), 6.30 (d, J = 7.6 Hz, 1H), 6.35 (d, J = 9.6 Hz, 1H),2.43 (s, 3H) 411 400 MHz 12.15 (br. s., 1H), 9.0 (d, J = 8.4 Hz, 1H),8.13 (d, J = 2.4 Hz, DMSO-d₆ 1H), 7.92 (dd, J = 10.0, 2.8 Hz, 1H),7.47-7.58 (m, 2H), 7.36-7.39 (m, 2H), 7.27 (d, J = 8.8 Hz, 1H),7.17-7.22 (m, 2H), 6.34-6.38 (m, 2H) 412 400 MHz 12.13 (br. s., 1H),9.08 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 2.4 Hz, DMSO-d₆ 1H), 7.91 (dd, J= 9.6, 2.4 Hz, 1H), 7.56-7.58 (m, 1H), 7.41-7.52 (m, 2H), 7.16-7.25 (m,3H), 6.59 (d, J = 7.6 Hz, 1H), 6.36 (d, J = 9.6 Hz, 1H) 413 400 MHz12.15 (br. s., 1H), 9.05 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 2.4 Hz,DMSO-d₆ 1H), 7.93 (dd, J = 9.6, 2.4 Hz, 1H), 7.57-7.61 (m, 1H),7.47-7.49 (m, 1H), 7.37-7.43 (m, 1H), 7.23-7.34 (m, 2H), 7.13-7.17 (m,1H), 6.55 (d, J = 8.0 Hz, 1H), 6.37 (d, J = 9.6 Hz, 1H) 414 400 MHz12.14 (br. s., 1H), 9.04 (d, J = 7.6 Hz, 1H), 8.17 (d, J = 2.0 Hz,DMSO-d₆ 1H), 7.93 (dd, J = 9.6, 2.4 Hz, 1H), 7.58-7.62 (m, 1H),7.49-7.52 (m, 1H), 7.24-7.33 (m, 4H), 6.56 (d, J = 8.0 Hz, 1H), 6.38 (d,J = 9.6 Hz, 1H) 415 400 MHz 8.52 (br. s., 1H), 8.36 (d, J = 7.8 Hz, 2H),8.12-8.24 (m, 1H), d₄-MeOH 7.67 (t, J = 8.9 Hz, 1H), 7.32-7.55 (m, 4H),6.77 (br. s., 1H) 416 300 MHz 8.44-8.56 (m, 2H), 7.71 (dd, J = 6.3, 2.2Hz, 1H), 7.63 (ddd, J = 9.9, d₄-MeOH 8.5, 1.2 Hz, 1H), 7.35-7.49 (m,5H), 6.66 (d, J = 1.6 Hz, 1H), 6.59 (dd, J = 7.2, 6.4 Hz, 1H) 417 400MHz 12.15 (br. s., 1H), 9.01 (d, J = 8.0 Hz, 1H), 8.14 (br. s., 1H),DMSO-d₆ 7.91 (d, J = 9.6 Hz, 1H), 7.49-7.59 (m, 3H), 7.12-7.31 (m, 4H),6.40 (dd, J = 14.4, 10.0 Hz, 2H) 418 400 MHz 12.12 (br. s., 1H), 9.04(d, J = 7.2 Hz, 1H), 8.18 (d, J = 2.4 Hz, DMSO-d₆ 1H), 7.92 (dd, J =9.6, 2.4 Hz, 1H), 7.53-7.57 (m, 1H), 7.45-7.49 (m, 2H), 7.12-7.18 (m,3H), 6.64 (d, J = 7.2 Hz, 1H), 6.34 (d, J = 9.6 Hz, 1H) 419 300 MHz 8.48(dt, J = 4.7, 1.3 Hz, 1H), 8.14 (dd, J = 2.7, 0.5 Hz, 1H), d₄-MeOH 8.04(dd, J = 9.6, 2.7 Hz, 1H), 7.63 (ddd, J = 9.8, 8.4, 1.3 Hz, 1H),7.34-7.51 (m, 3H), 7.25-7.34 (m, 1H), 6.65 (s, 1H), 6.53 (dd, J = 9.6,0.6 Hz, 1H) 420 400 MHz 12.05 (br. s., 1H), 8.96 (d, J = 8.0 Hz, 1H),8.14 (br. s., 1H), DMSO-d₆ 7.92 (d, J = 11.6 Hz, 1H), 7.70 (t, J = 8.0Hz, 1H), 7.61-7.52 (m, 2H), 7.38 (d, J = 8.0 Hz, 1H ), 7.06 (d, J = 7.2Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.37 (d, J = 9.6 Hz, 1H), 6.29 (d, J= 8.0 Hz, 1H), 3.81 (s, 3H) 421 400 MHz 12.02 (br. s., 1H), 9.01 (d, J =8.4 Hz, 1H), 8.26 (d, J = 2.4 Hz, DMSO-d₆ 1H), 8.15 (br. s., 1H), 7.92(dd, J = 9.6, 2.4 Hz, 1H), 7.51-7.54 (m, 2H), 7.41-7.45 (m, 2H), 7.31(d, J = 8.4 Hz, 1H), 6.37 (dd, J = 9.2, 5.6 Hz, 2H), 3.81 (s, 3H) 422400 MHz 12.05 (br. s., 1H), 9.01 (d, J = 8.0 Hz, 1H), 8.37 (d, J = 5.6Hz, DMSO-d₆ 1H), 8.16 (d, J = 2.4 Hz, 1H), 7.92 (dd, J = 9.6, 2.8 Hz,1H), 7.50-7.58 (m, 2H), 7.35 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 2.4 Hz,1H), 6.92 (dd, J = 6.0, 2.8 Hz, 1H), 6.36 (dd, J = 8.0, 3.2 Hz, 2H),3.82 (s, 3H) 423 400 MHz 12.02 (br. s., 1H), 9.03 (d, J = 8.2 Hz, 1H),8.42 (d, J = 4.9 Hz, DMSO-d₆ 1H), 8.17 (d, J = 2.2 Hz, 1H), 7.93 (dd, J= 9.7, 2.6 Hz, 1H), 7.46-7.62 (m, 2H), 7.30-7.44 (m, 2H), 7.17 (d, J =4.7 Hz, 1H), 6.25-6.44 (m, 2H), 2.34 (s, 3H) 424 400 MHz 12.00 (br. s.,1H), 9.01 (d, J = 8.0 Hz, 1H), 8.33-8.48 (m, 1H), DMSO-d₆ 8.15 (d, J =2.5 Hz, 1H), 7.91 (dd, J = 9.6, 2.8 Hz, 1H), 7.63 (dd, J = 8.0, 1.8 Hz,1H), 7.46-7.59 (m, 2H), 7.40 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 8.5 Hz,1H), 6.36 (dd, J = 8.9, 4.5 Hz, 2H), 2.28 (s, 3H)

Stereochemistry

Absolute stereochemistry, where noted, was determined by comparison ofeither (I) quantum-mechanically predicted optical rotation values(Stephens, P. J. et. al, J. Phys. Chem. A 2001, 105, 5356) or (II) VCDspectra (Stephens, P. J. et. al, Chirality 2008, 20, 643) to thosemeasured experimentally. A single-crystal X-ray structure of(S)-tert-butyl((3-bromopyridin-2-yl)(4-(trifluoromethyl)phenyl)-methyl)carbamate(Intermediate 46, Step 5) provided confirmation of the absolutestereochemistry.

Computed and observed optical rotation for a subset of examples in thisinvention are shown in Table 7. Optical rotations were measured in CHCl₃at room temperature using a Perkin-Elmer digital polarimeter at 589 nm(sodium D line) in a 1.0 dm cell.

TABLE 7 Computed and Measured Optical Rotation for AbsoluteStereochemistry Assignment Computed Measured Example Rotation Rotation41 (S) = + +78° 50 (S) = + +57° 92 (S) = + +16°

The experimental vibrational circular dichroism (VCD) spectrum ofExample 28 was obtained on a Biotools, Inc. ChiralIR spectrometer (BaF2cell, 100 um path length, 48 mg/mL, 4 h acquisition time in CDCl₃).Comparison of the experimental spectrum to those computed quantummechanically for the (S) and (R) stereoisomers, using the B3LYP hybriddensity functional and 6-31G* basis set, led to the assignment of 28 asthe (S) configuration.

Assays

Luminescence Readout Assay for Measuring Intracellular Calcium.

A stable Chinese hamster ovary cell line expressing human TRPM8 wasgenerated using tetracycline inducible T-REx™ expression system fromInvitrogen, Inc. (Carlsbad, Calif.). In order to enable a luminescencereadout based on intracellular increase in calcium (Le Poul et al.,2002), the cell line was also co-transfected with pcDNA3.1 plasmidcontaining jelly fish aequorin cDNA. Twenty four hours before the assay,cells were seeded in 96-well plates and TRPM8 expression was inducedwith 0.5 μg/mL tetracycline. On the day of the assay, culture media wasremoved and cells were incubated with assay buffer (Ham's F12 containing30 mM HEPES) that contained 15 μM coelenterazine (P. J. K, Germany) for2 h. Potential antagonists were added 2.5 min prior to the addition ofagonist, 1 μM icilin, 100 μM L-menthol, or 1 min prior to the additionof cold buffer (<10° C.). The luminescence was measured by a CCD camerabased FLASH-luminometer built by Amgen, Inc. A cooling device attachedto FLASH luminometer was used for cold activation. Compound activity wascalculated using either GraphPad Prism 4.01 (GraphPad Software Inc, SanDiego, Calif.) or Genedata Screener.

The following compounds exhibit IC₅₀ values of less than 10 μM in theassay described above with icilin activation. Results are shown in Table8.

TABLE 8 hTRPM8 IC_(5o)'s for Examples 1-438 Example IC₅₀ (μM) 1 0.0098 20.0170 3 0.0177 4 0.0440 5 0.0219 6 0.0739 7 0.0758 8 0.0543 9 0.146 100.0205 11 0.0785 12 0.0754 13 0.0833 14 0.0749 15 0.117 16 0.0807 170.230 18 0.157 19 0.0952 20 0.187 21 0.0918 22 0.418 23 1.06 24 0.318 250.0368 26 3.29 27 0.129 28 0.194 29 0.0324 30 0.0149 31 0.162 32 0.14333 0.125 34 0.0322 35 0.0196 36 0.073 37 0.146 38 0.0777 39 0.0178 400.0134 41 0.0063 42 0.0539 43 0.0245 44 0.229 45 0.0635 46 0.0123 470.0201 48 0.0215 49 0.127 50 0.0105 51 0.0101 52 0.0401 53 0.0455 540.0231 55 0.0304 56 0.0092 57 0.0631 58 0.0639 59 0.0416 60 0.0784 610.312 62 0.172 63 0.134 64 0.02 65 0.245 66 0.405 67 0.04 68 0.0142 690.0129 70 0.0152 71 0.0092 72 0.167 73 0.017 74 0.0853 75 0.0391 760.0045 77 0.053 78 0.0148 79 0.0051 80 0.0231 81 0.0248 82 0.0177 830.0392 84 0.0053 85 0.0289 86 0.0102 87 0.0089 88 0.0121 89 0.0103 900.0062 91 0.0137 92 0.0103 93 0.0178 94 0.0414 95 0.0572 96 0.0376 970.119 98 0.125 99 0.129 100 0.0615 101 0.395 102 0.0081 103 0.0078 1040.0062 105 0.0108 106 0.0089 107 0.0267 108 0.0241 109 0.0639 110 0.0644111 0.0559 112 0.0844 113 0.0311 114 0.0506 115 0.0562 116 0.0429 1170.0700 118 0.0905 119 0.100 120 0.0594 121 0.247 122 0.107 123 0.149 1240.190 125 0.176 126 0.194 127 0.584 128 0.125 129 0.114 130 0.0247 1310.0189 132 0.0175 133 0.0200 134 0.0310 135 0.0194 136 0.121 137 0.0949138 0.0464 139 0.0659 140 0.0527 141 0.160 142 0.144 143 0.0874 1440.200 145 0.0852 146 0.180 147 0.148 148 0.257 149 0.398 150 0.178 1510.395 152 0.459 153 0.373 154 2.53 155 1.44 156 0.301 157 0.716 158 1.95159 2.21 160 3.32 161 3.37 162 4.38 163 3.18 164 0.294 165 0.0051 1660.0076 167 0.0215 168 0.0384 169 0.0104 170 0.0235 171 0.0173 172 0.0181173 0.0153 174 0.0229 175 0.0303 176 0.0219 177 0.0208 178 0.0262 1790.0398 180 0.0297 181 0.0266 182 0.0418 183 0.0396 184 0.0529 185 0.0290186 0.0492 187 0.0453 188 0.0351 189 0.0806 190 0.0331 191 0.0789 1920.0790 193 0.0348 194 0.0756 195 0.0506 196 0.0671 197 0.115 198 0.0560199 0.0776 200 0.0493 201 0.0293 202 0.0352 203 0.135 204 0.104 2050.140 206 0.0675 207 0.121 208 0.0417 209 0.105 210 0.150 211 0.115 2120.0815 213 0.0430 214 0.121 215 0.0845 216 0.143 217 0.147 218 0.230 2190.137 220 0.164 221 0.105 222 0.119 223 0.599 224 1.4 225 0.487 226 2.31227 0.0414 228 0.0397 229 0.354 230 0.0837 231 0.461 232 0.0159 2330.0831 234 0.169 235 0.226 236 0.239 237 0.733 238 0.547 239 0.016 2400.081 241 0.59 242 1.03 243 1.44 244 3.38 245 0.0774 246 0.210 2470.0427 248 0.0119 249 0.0132 250 0.0192 251 0.0193 252 0.0247 253 0.0114254 0.0118 255 0.0176 256 0.302 257 0.109 258 0.0407 259 0.128 260 0.311261 0.375 262 0.114 263 0.133 264 0.253 265 0.0622 266 0.223 267 0.0099268 0.156 269 0.136 270 0.0191 271 0.0089 272 0.0119 273 0.0161 2740.198 275 0.0686 276 0.177 277 0.188 278 0.317 279 1.81 280 0.0221 2810.0101 282 0.0117 283 0.0218 284 0.346 285 2.16 286 1.11 287 2.37 2880.139 289 1.61 290 0.944 291 0.332 292 0.0524 293 0.0137 294 0.0145 2950.0180 296 0.0231 297 0.0168 298 0.0361 299 0.0175 300 0.0697 301 0.0417302 0.0709 303 0.143 304 0.0144 305 0.0296 306 0.389 307 0.0454 3080.0269 309 0.0308 310 0.0160 311 0.0278 312 0.0252 313 0.0259 314 0.0218315 0.0363 316 0.0314 317 0.0389 318 0.0297 319 0.132 320 0.132 3210.164 322 0.202 323 0.0367 324 1.05 325 0.644 326 3.21 327 0.302 3281.06 329 0.841 330 2.68 331 0.965 332 0.268 333 0.658 334 0.103 3350.209 336 0.136 337 0.313 338 0.264 339 0.915 340 0.808 341 4.28 3420.255 343 1.48 344 0.0451 345 0.102 346 0.0111 347 0.0100 348 0.0154 3490.0156 350 0.0227 351 0.0159 352 0.0188 353 0.0277 354 0.0681 355 0.0385356 0.0784 357 0.0466 358 0.0141 359 0.0136 360 0.0200 361 0.0058 3620.0042 363 0.0295 364 0.0158 365 0.0401 366 0.0097 367 0.0683 368 0.0210369 3.71 370 0.0337 371 0.190 372 0.0894 373 0.0206 374 0.0524 3750.0303 376 0.0530 377 0.0207 378 0.0503 379 0.270 380 0.245 381 0.0104382 0.0069 383 0.0079 384 0.0058 385 0.0067 386 0.0105 387 0.279 3882.98 389 0.0183 390 0.136 391 0.0117 392 0.0076 393 0.0061 394 0.0354395 0.0066 396 0.0201 397 0.0103 398 0.189 399 0.0165 400 0.0069 4010.0128 402 0.120 403 0.0178 404 3.55 405 0.0175 406 0.241 407 0.0596 4080.0781 409 0.0892 410 0.0718 411 0.14 412 0.048 413 0.197 414 0.150 4150.648 416 0.054 417 0.083 418 0.065 419 2.02 420 0.118 421 0.611 4220.841 423 0.137 424 0.092 425 0.0105 426 0.0097 427 0.0140 428 1.29 4292.66 430 0.0124 431 0.0564 432 0.0195 433 0.0079 434 0.0121 435 6.24 4360.0224 437 0.225 438 0.0114

Icilin Biochemical Challenge Models

Inhibition of Icilin Induced Lumping in Mice

Example compounds at doses ranging from 0.01 to 10 mg/kg wereadministered to male C57BL/6 mice (18-25 g, Taconic, n=10/treatment) 1 hbefore icilin to assess the ability to block the spontaneous jumpsinduced by icilin (i.p. suspended in 100% PEG400 at 20 mg/kg, 5 mL/kg).The total number of jumps were recorded during the 10 min post-icilinadministration based on the number of photocell beam breaks from thevertical array of open field boxes (Kinder Scientific) while movement ofthe mice was restricted within a clear Plexiglas® cylinder 9.5 cmdiameter×30 cm height.

Inhibition of Icilin Induced Shaking in Rats

Example compounds at doses ranging from 0.01 to 3 mg/kg (p.o, suspendedin 5% Tween80/Oralplus or suspended in 2% HPMC-1% Tween-80 pH2.2 withMSA, 5 mL/kg) were administered to male Sprague Dawley rats (200-300 g,Harlan, n=6-8/treatment) 2 h before icilin to assess the ability toblock the spontaneous wet-dog shake phenomena induced by icilin (i.p.,suspended in 100% PEG400 at 0.5 mg/kg, 1 mL/kg or p.o., suspended in 2%HPMC-1% Tween-80 at 3 mg/kg, 2.5 mL/kg). Spontaneous wet-dog shakes werecounted manually by two blinded observers or using LABORAS automation(Metris) for 30 min post-icilin. Results are shown in Table 9.

TABLE 9 Inhibition of icilin induced wet dog shakes in rats by selectExamples % Inhibition % Inhibition Dose of Wet-Dog Dose of Wet-DogExample # (mg/kg) Shakes Example (mg/kg) Shakes 1 1 100 297 1 78 51 1 99299 1 56 68 1 100 348 1 51 76 1 100 362 1 98 79 1 99 370 1 50 91 1 100373 1 64 102 1 99 377 1 94 103 1 97 386 1 97 132 1 95 426 1 53 293 1 96432 1 60 295 1 77 434 1 91

Cold Pressor Test (CPT) as a Translatable PD Model for TRPM8

The cold pressor test (CPT) was developed as a method to measure bloodpressure response following exposure to a cold stimulus and has beenused over 70 years in the diagnosis of hypertension and other cardiacautonomic disorders (Hines and Brown 1936). In healthy human subjects,the CPT is typically performed by immersing a subject's hand into icewater (0-5° C.) which triggers, through a vascular sympatheticactivation of afferent pain and temperature neurons, an increase inblood pressure. With some modifications, this test has also beenutilized in rat to delineate the medullary and spinal pathways mediatingthe cardio-vascular responses to cold pressor test and to identifyneurotransmitters in these pathways (Sapru N et al 2008) or tocharacterize analgesic compounds (Koltzenburg M et al 2006 and Player MR et al 2011).

TRPM8 antagonists were evaluated in rat CPT to determine whether TRPM8antagonists would attenuate the increase in blood pressure resultingfrom exposure to cold stimulation of the paws and ventral half of thebody. Male Sprague-Dawley rats weighing 350-450 g were instrumented witha unilateral carotid artery-cannula connected to a transducer formeasuring blood pressure using a Digi-Med Blood Pressure Analyzer, Model400. Animals were orally administrated with Vehicle (2% HPMC 1% Tween 80pH 2.2 with MSA) or test compounds at 120 min prior to cold challengeand anesthetized with sodium pentobarbital at 60 mg/kg ip at 100 minprior to cold. Blood pressure was recorded for 5 min for pre-coldbaseline and additional 5 min during immersion of the paws and ventralhalf of body in ice water. Percent inhibition attributed to treatmentwith test compound was then determined using the following Formula:[1−(cold evoked change in MBP/cold evoked change in MBPpost-vehicle)]×100. Plasma was collected through artery catheterimmediately after CPT for pk analysis and IC50/90 determination.

REFERENCES

-   Hines, E A and Brown G E. The cold pressor test for measuring the    reactability of the blood pressure. Am. Heart J. 1936, 11:1-9-   Nakamura T, Kawabe K, and Sapru H N. Cold pressor test in the rat:    medullary and spinal pathways and neurotransmitters. Am J Physiol    Heart Circ Physiol 2008, 295:H1780-H1787-   Koltzenburg M, Pokorny R, Gasser U and Richarz U. Differential    sensitivity of three experimental pain models in detecting the    analgesic effects of transdermal fentanyl and buprenorphine. Pain    2006, 126:165-174-   Parks D, Parsons W, Colburn R, Meegala S, Ballentine S, Illig C, Qin    N, Liu Y, Hutchinson T, Lubin M, Stone D, Baker J, Schneider C, Ma    J, Damiano B, Flores C, and Player M. Design and optimization of    benzimidazole-containing transient receptor potentiate melastatin 8    (TRPM8) antagonists. J. Med. Chem. 2011, 54:233-247

CCI Model

Surgery—A chronic constriction injury (CCI) can be produced aspreviously described (Bennett & Xie, 1988). Under gaseous anesthesiawith a mixture of isoflurane (3% for induction and 2% for maintenance)in O₂, the sciatic nerve can be exposed at the mid-thigh level proximalto the sciatic trifurcation. Four chromic gut ligatures (4-0) can betied loosely around nerve, 1-2 mm apart such that the vascular supplywill not be compromised.Behavioral testing—A behavioral test can be performed to estimatecold-induced ongoing pain as previously described (Choi et al., 1994).The rat can be placed under a transparent plastic cover on an aluminumplate (IITC PE34, Woodland, Calif.) which can be kept at a coldtemperature (5±0.5° C.). After 2 min of adaptation, the cumulativeduration of time that the rat lifts its foot off the plate for the next5 min can be measured. Foot lifts associated with locomotion or groomingare not counted. Seven to 9 days after the CCI surgery, baseline of thecold-induced ongoing pain can be measured. Any rat showing acold-induced ongoing pain less than 100 sec out of 300 sec observationperiod can be eliminated from the study. Twenty four hours after thebaseline measurement, test compound, positive control, morphine (2mg/kg, Sigma, St. Louis) or a vehicle (saline or 2% HPMC/1% Tween 80)can be administered orally (test compound) or subcutaneously (morphine).Two hours (test compound) or 30 mins (morphine) after the drugadministration, the cold-induced ongoing pain can be measured again.

Chung Model

Surgery—Spinal nerve ligation surgery can be performed as previouslydescribed (Kim & Chung, 1992). Briefly, under gaseous anesthesia with amixture of isoflurane (3% for induction and 2% for maintenance) in O₂,the spinal nerve injury can be produced by ligating the left L5 and L6spinal nerves taking special care to avoid any possible damage to the L4spinal nerve or surrounding area. Additional treatments can be performedto increase the development of mechanical allodynia. First, L5 spinalnerve can be cut approximately 1 mm distal to the suture as described byLi et al. (2000). Second, immediately after ligation and cut, the L4spinal nerve can be lightly manipulated by slightly stretching it with afine hooked glass rod and gently sliding the hook back and forth 20times along the nerve as described by Lee et al. (2003). The wholesurgery procedure from anesthesia to the clipping of the incised skincan take at most 15 min.Behavioral testing—Two weeks later, mechanical sensitivity can bemeasured by determining the median 50% foot withdrawal threshold for vonFrey filaments using the up-down method (Chaplan et al., 1994). The ratscan be placed under a plastic cover (9×9×20 cm) on a metal mesh floor.The area tested consists of the middle glabrous area between thefootpads of the plantar surface of the hind paw. The plantar area can betouched with a series of 9 von Frey hairs with approximatelyexponentially incremental bending forces (von Frey values: 3.61, 3.8,4.0, 4.2, 4.41, 4.6, 4.8, 5.0 and 5.2; equivalent to: 0.41, 0.63, 1.0,1.58, 2.51, 4.07, 6.31, 10 and 15.8 g). The von Frey hair can bepresented perpendicular to the plantar surface with sufficient force tocause slight bending, and held for approximately 3-4 sec. Abruptwithdrawal of the foot (paw flinching, shaking or licking for more than1 sec) can be recorded as a response. Any rat showing a mechanicalthreshold of more than 3.16 g or less than 0.7 g after surgery can beeliminated from the study. After measuring basal threshold, testcompound, positive control gabapentin (Sigma, St. Louis) or a vehicle(saline or 2% HPMC/1% Tween 80) can be administered orally (testcompound) or intraperitoneally (gabapentin). The measurement of thetactile threshold can be reassessed at 1.5 and 2 h after drugadministration.Data—Since the von Frey filament set is calibrated on a logarithmicscale by the vendor (Stoelting) and our selection of 9 filaments for theup-down method is also based on near equal logarithmic intervals (Dixonet al., 1980), data can be treated using logarithmic values in everyaspect (statistical treatment as well as plotting). However, anequivalent gram value scale is labeled on the Y-axis of the figures forconvenience. Data are expressed as mean±standard error of the mean(S.E.M.).

For the treatment of TRPM8-receptor-diseases, such as acute,inflammatory and neuropathic pain, dental pain, general headache,migraine, cluster headache, mixed-vascular and non-vascular syndromes,tension headache, general inflammation, arthritis, rheumatic diseases,osteoarthritis, inflammatory bowel disorders, inflammatory eyedisorders, inflammatory or unstable bladder disorders, psoriasis, skincomplaints with inflammatory components, chronic inflammatoryconditions, inflammatory pain and associated hyperalgesia and allodynia,neuropathic pain and associated hyperalgesia and allodynia, diabeticneuropathy pain, causalgia, sympathetically maintained pain,deafferentation syndromes, asthma, epithelial tissue damage ordysfunction, herpes simplex, disturbances of visceral motility atrespiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritus, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladderdisorders, the compounds of the present invention may be administeredorally, parentally, by inhalation spray, rectally, or topically indosage unit formulations containing conventional pharmaceuticallyacceptable carriers, adjuvants, and vehicles. The term parenteral asused herein includes, subcutaneous, intravenous, intramuscular,intrasternal, infusion techniques or intraperitoneally.

Treatment of diseases and disorders herein is intended to also includethe prophylactic administration of a compound of the invention, apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman) believed to be in need of preventative treatment, such as, forexample, pain, inflammation and the like.

The dosage regimen for treating TRPM8-receptor-mediated diseases,cancer, and/or hyperglycemia with the compounds of this invention and/orcompositions of this invention is based on a variety of factors,including the type of disease, the age, weight, sex, medical conditionof the patient, the severity of the condition, the route ofadministration, and the particular compound employed. Thus, the dosageregimen may vary widely, but can be determined routinely using standardmethods. Dosage levels of the order from about 0.01 mg to 30 mg perkilogram of body weight per day, preferably from about 0.1 mg to 10mg/kg, more preferably from about 0.25 mg to 1 mg/kg are useful for allmethods of use disclosed herein.

The pharmaceutically active compounds of this invention can be processedin accordance with conventional methods of pharmacy to produce medicinalagents for administration to patients, including humans and othermammals.

For oral administration, the pharmaceutical composition may be in theform of, for example, a capsule, a tablet, a suspension, or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a given amount of the active ingredient. For example,these may contain an amount of active ingredient from about 1 to 2000mg, preferably from about 1 to 500 mg, more preferably from about 5 to150 mg. A suitable daily dose for a human or other mammal may varywidely depending on the condition of the patient and other factors, but,once again, can be determined using routine methods.

The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water.The daily parenteral dosage regimen will be from about 0.1 to about 30mg/kg of total body weight, preferably from about 0.1 to about 10 mg/kg,and more preferably from about 0.25 mg to 1 mg/kg.

Injectable preparations, such as sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known areusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable non-irritating excipient such as cocoabutter and polyethylene glycols that are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

A suitable topical dose of active ingredient of a compound of theinvention is 0.1 mg to 150 mg administered one to four, preferably oneor two times daily. For topical administration, the active ingredientmay comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight ofthe formulation, although it may comprise as much as 10% w/w, butpreferably not more than 5% w/w, and more preferably from 0.1% to 1% ofthe formulation.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin(e.g., liniments, lotions, ointments, creams, or pastes) and dropssuitable for administration to the eye, ear, or nose.

For administration, the compounds of this invention are ordinarilycombined with one or more adjuvants appropriate for the indicated routeof administration. The compounds may be admixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, stearic acid, talc,magnesium stearate, magnesium oxide, sodium and calcium salts ofphosphoric and sulfuric acids, acacia, gelatin, sodium alginate,polyvinyl-pyrrolidine, and/or polyvinyl alcohol, and tableted orencapsulated for conventional administration. Alternatively, thecompounds of this invention may be dissolved in saline, water,polyethylene glycol, propylene glycol, ethanol, corn oil, peanut oil,cottonseed oil, sesame oil, tragacanth gum, and/or various buffers.Other adjuvants and modes of administration are well known in thepharmaceutical art. The carrier or diluent may include time delaymaterial, such as glyceryl monostearate or glyceryl distearate alone orwith a wax, or other materials well known in the art.

The pharmaceutical compositions may be made up in a solid form(including granules, powders or suppositories) or in a liquid form(e.g., solutions, suspensions, or emulsions). The pharmaceuticalcompositions may be subjected to conventional pharmaceutical operationssuch as sterilization and/or may contain conventional adjuvants, such aspreservatives, stabilizers, wetting agents, emulsifiers, buffers etc.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose, lactose, or starch. Such dosage forms may also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting, sweetening,flavoring, and perfuming agents.

Compounds of the present invention can possess one or more asymmetriccarbon atoms and are thus capable of existing in the form of opticalisomers as well as in the form of racemic or non-racemic mixturesthereof. The optical isomers can be obtained by resolution of theracemic mixtures according to conventional processes, e.g., by formationof diastereoisomeric salts, by treatment with an optically active acidor base. Examples of appropriate acids are tartaric, diacetyltartaric,dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and thenseparation of the mixture of diastereoisomers by crystallizationfollowed by liberation of the optically active bases from these salts. Adifferent process for separation of optical isomers involves the use ofa chiral chromatography column optimally chosen to maximize theseparation of the enantiomers. Still another available method involvessynthesis of covalent diastereoisomeric molecules by reacting compoundsof the invention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds of theinvention can likewise be obtained by using active starting materials.These isomers may be in the form of a free acid, a free base, an esteror a salt.

Likewise, the compounds of this invention may exist as isomers, that iscompounds of the same molecular formula but in which the atoms, relativeto one another, are arranged differently. In particular, the alkylenesubstituents of the compounds of this invention, are normally andpreferably arranged and inserted into the molecules as indicated in thedefinitions for each of these groups, being read from left to right.However, in certain cases, one skilled in the art will appreciate thatit is possible to prepare compounds of this invention in which thesesubstituents are reversed in orientation relative to the other atoms inthe molecule. That is, the substituent to be inserted may be the same asthat noted above except that it is inserted into the molecule in thereverse orientation. One skilled in the art will appreciate that theseisomeric forms of the compounds of this invention are to be construed asencompassed within the scope of the present invention.

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. The salts include, but are notlimited to, the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methansulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 2-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate, andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids that may be employed to from pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulfuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Otherexamples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases.

Also encompassed in the scope of the present invention arepharmaceutically acceptable esters of a carboxylic acid or hydroxylcontaining group, including a metabolically labile ester or a prodrugform of a compound of this invention. A metabolically labile ester isone which may produce, for example, an increase in blood levels andprolong the efficacy of the corresponding non-esterified form of thecompound. A prodrug form is one which is not in an active form of themolecule as administered but which becomes therapeutically active aftersome in vivo activity or biotransformation, such as metabolism, forexample, enzymatic or hydrolytic cleavage. For a general discussion ofprodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examplesof a masked carboxylate anion include a variety of esters, such as alkyl(for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl),aralkyl (for example, benzyl, p-methoxybenzyl), andalkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have beenmasked as arylcarbonyloxymethyl substituted derivatives which arecleaved by esterases in vivo releasing the free drug and formaldehyde(Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidicNH group, such as imidazole, imide, indole and the like, have beenmasked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs,Elsevier (1985)). Hydroxy groups have been masked as esters and ethers.EP 039,051 (Sloan and Little, Apr. 11, 1981) discloses Mannich-basehydroxamic acid prodrugs, their preparation and use. Esters of acompound of this invention, may include, for example, the methyl, ethyl,propyl, and butyl esters, as well as other suitable esters formedbetween an acidic moiety and a hydroxyl containing moiety. Metabolicallylabile esters, may include, for example, methoxymethyl, ethoxymethyl,iso-propoxymethyl, α-methoxyethyl, groups such asα-((C₁-C₄)alkyloxy)ethyl, for example, methoxyethyl, ethoxyethyl,propoxyethyl, iso-propoxyethyl, etc.; 2-oxo-1,3-dioxolen-4-ylmethylgroups, such as 5-methyl-2-oxo-1,3, dioxolen-4-ylmethyl, etc.; C₁-C₃alkylthiomethyl groups, for example, methylthiomethyl, ethylthiomethyl,isopropylthiomethyl, etc.; acyloxymethyl groups, for example,pivaloyloxymethyl, α-acetoxymethyl, etc.; ethoxycarbonyl-1-methyl; orα-acyloxy-α-substituted methyl groups, for example α-acetoxyethyl.

Further, the compounds of the invention may exist as crystalline solidswhich can be crystallized from common solvents such as ethanol,N,N-dimethyl-formamide, water, or the like. Thus, crystalline forms ofthe compounds of the invention may exist as polymorphs, solvates and/orhydrates of the parent compounds or their pharmaceutically acceptablesalts. All of such forms likewise are to be construed as falling withinthe scope of the invention.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more compounds of the invention or other agents. Whenadministered as a combination, the therapeutic agents can be formulatedas separate compositions that are given at the same time or differenttimes, or the therapeutic agents can be given as a single composition.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A compound having the formula

or a pharmaceutically-acceptable salt thereof.
 2. The compound of claim1 in a neutral form.
 3. The pharmaceutically-acceptable salt of thecompound of claim
 1. 4. A pharmaceutical formulation, the pharmaceuticalformulation comprising the compound of claim 1 or thepharmaceutically-acceptable salt thereof, and apharmaceutically-acceptable diluent or carrier.
 5. A compound having theformula

or a pharmaceutically-acceptable salt thereof.
 6. The compound of claim5 in a neutral form.
 7. The pharmaceutically-acceptable salt of thecompound of claim
 5. 8. A pharmaceutical formulation, the pharmaceuticalformulation comprising the compound of claim 5 or thepharmaceutically-acceptable salt thereof, and apharmaceutically-acceptable diluent or carrier.
 9. A compound having theformula

or a pharmaceutically-acceptable salt thereof.
 10. The compound of claim9 in a neutral form.
 11. The pharmaceutically-acceptable salt of thecompound of claim
 9. 12. A pharmaceutical formulation, thepharmaceutical formulation comprising the compound of claim 9 or thepharmaceutically-acceptable salt thereof, and apharmaceutically-acceptable diluent or carrier.
 13. A compound havingthe formula

or a pharmaceutically-acceptable salt thereof.
 14. The compound of claim13 in a neutral form.
 15. The pharmaceutically-acceptable salt of thecompound of claim
 13. 16. A pharmaceutical formulation, thepharmaceutical formulation comprising the compound of claim 13 or thepharmaceutically-acceptable salt thereof, and apharmaceutically-acceptable diluent or carrier.
 17. A compound havingthe formula

or a pharmaceutically-acceptable salt thereof.
 18. The compound of claim17 in a neutral form.
 19. The pharmaceutically-acceptable salt of thecompound of claim
 17. 20. A pharmaceutical formulation, thepharmaceutical formulation comprising the compound of claim 17 or thepharmaceutically-acceptable salt thereof, and apharmaceutically-acceptable diluent or carrier.
 21. A compound havingthe formula

or a pharmaceutically-acceptable salt thereof.
 22. The compound of claim21 in a neutral form.
 23. The pharmaceutically-acceptable salt of thecompound of claim
 21. 24. A pharmaceutical formulation, thepharmaceutical formulation comprising the compound of claim 21 or thepharmaceutically-acceptable salt thereof, and apharmaceutically-acceptable diluent or carrier.
 25. A compound havingthe formula

or a pharmaceutically-acceptable salt thereof.
 26. The compound of claim25 in a neutral form.
 27. The pharmaceutically-acceptable salt of thecompound of claim
 25. 28. A pharmaceutical formulation, thepharmaceutical formulation comprising the compound of claim 25 or thepharmaceutically-acceptable salt thereof, and apharmaceutically-acceptable diluent or carrier.
 29. A compound havingthe formula

or a pharmaceutically-acceptable salt thereof.
 30. The compound of claim29 in a neutral form.
 31. The pharmaceutically-acceptable salt of thecompound of claim
 29. 32. A pharmaceutical formulation, thepharmaceutical formulation comprising the compound of claim 29 or thepharmaceutically-acceptable salt thereof, and apharmaceutically-acceptable diluent or carrier.
 33. A compound havingthe formula

or a pharmaceutically-acceptable salt thereof, a tautomer thereof, or apharmaceutically-acceptable salt of the tautomer.
 34. The compound orthe tautomer of claim 33 in a neutral form.
 35. Thepharmaceutically-acceptable salt of the compound or thepharmaceutically-acceptable salt of the tautomer of claim
 33. 36. Apharmaceutical formulation, the pharmaceutical formulation comprisingthe compound of claim 33 or the pharmaceutically-acceptable saltthereof, the tautomer thereof, or the pharmaceutically-acceptable saltof the tautomer, and a pharmaceutically-acceptable diluent or carrier.37. A compound having the formula

or a pharmaceutically-acceptable salt thereof, a tautomer thereof, or apharmaceutically-acceptable salt of the tautomer.
 38. The compound orthe tautomer of claim 37 in a neutral form.
 39. Thepharmaceutically-acceptable salt of the compound or thepharmaceutically-acceptable salt of the tautomer of claim
 37. 40. Apharmaceutical formulation, the pharmaceutical formulation comprisingthe compound of claim 37 or the pharmaceutically-acceptable saltthereof, the tautomer thereof, or the pharmaceutically-acceptable saltof the tautomer, and a pharmaceutically-acceptable diluent or carrier.